Cannabinoid receptor ligands and uses thereof

ABSTRACT

Compounds of Formula (I) that act as cannabinoid receptor ligands and their uses in the treatment of diseases linked to the mediation of the cannabinoid receptors in animals are described herein.

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/464,918, filed on Apr. 23, 2003 and 60/540,048, filedon Jan. 29, 2004, both of which are incorporated herein by reference intheir entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to pyrazolo[4,3-d]pyrimidine andpyrazolo[3,4-c]pyridine compounds as cannabinoid receptor ligands, inparticular CB1 receptor antagonists, and uses thereof for treatingdiseases, conditions and/or disorders modulated by cannabinoid receptorantagonists.

BACKGROUND

[0003] Obesity is a major public health concern because of itsincreasing prevalence and associated health risks. Obesity andoverweight are generally defined by body mass index (BMI), which iscorrelated with total body fat and estimates the relative risk ofdisease. BMI is calculated by weight in kilograms divided by height inmeters squared (kg/m²). Overweight is typically defined as a BMI of25-29.9 kg/m², and obesity is typically defined as a BMI of 30 kg/m².See, e.g., National Heart, Lung, and Blood Institute, ClinicalGuidelines on the Identification, Evaluation, and Treatment ofOverweight and Obesity in Adults, The Evidence Report, Washington, D.C.:U.S. Department of Health and Human Services, NIH publication no.98-4083 (1998).

[0004] The increase in obesity is of concern because of the excessivehealth risks associated with obesity, including coronary heart disease,strokes, hypertension, type 2 diabetes mellitus, dyslipidemia, sleepapnea, osteoarthritis, gall bladder disease, depression, and certainforms of cancer (e.g., endometrial, breast, prostate, and colon). Thenegative health consequences of obesity make it the second leading causeof preventable death in the United States and impart a significanteconomic and psychosocial effect on society. See, McGinnis M, Foege WH.,“Actual Causes of Death in the United States,” JAMA, 270, 2207-12(1993).

[0005] Obesity is now recognized as a chronic disease that requirestreatment to reduce its associated health risks. Although weight loss isan important treatment outcome, one of the main goals of obesitymanagement is to improve cardiovascular and metabolic values to reduceobesity-related morbidity and mortality. It has been shown that 5-10%loss of body weight can substantially improve metabolic values, such asblood glucose, blood pressure, and lipid concentrations. Hence, it isbelieved that a 5-10% intentional reduction in body weight may reducemorbidity and mortality.

[0006] Currently available prescription drugs for managing obesitygenerally reduce weight by inducing satiety or decreasing dietary fatabsorption. Satiety is achieved by increasing synaptic levels ofnorepinephrine, serotonin, or both. For example, stimulation ofserotonin receptor subtypes 1B, 1D, and 2C and 1- and 2-adrenergicreceptors decreases food intake by regulating satiety. See, Bray G A,“The New Era of Drug Treatment. Pharmacologic Treatment of Obesity:Symposium Overview,” Obes Res., 3(suppl 4), 415s-7s (1995). Adrenergicagents (e.g., diethylpropion, benzphetamine, phendimetrazine, mazindol,and phentermine) act by modulating central norepinephrine and dopaminereceptors through the promotion of catecholamine release. Olderadrenergic weight-loss drugs (e.g., amphetamine, methamphetamine, andphenmetrazine), which strongly engage in dopamine pathways, are nolonger recommended because of the risk of their abuse. Fenfluramine anddexfenfluramine, both serotonergic agents used to regulate appetite, areno longer available for use.

[0007] More recently, CB1 cannabinoid receptor antagonists/inverseagonists have been suggested as potential appetite suppressants. See,e.g., Arnone, M., et al., “Selective Inhibition of Sucrose and EthanolIntake by SR141716, an Antagonist of Central Cannabinoid (CB1)Receptors,” Psychopharmacol, 132, 104-106 (1997); Colombo, G., et al.,“Appetite Suppression and Weight Loss after the Cannabinoid AntagonistSR141716,” Life Sci., 63, PL113-PL117 (1998); Simiand, J., et al.,“SR141716, a CB1 Cannabinoid Receptor Antagonist, Selectively ReducesSweet Food Intake in Marmose,” Behav. Pharmacol., 9, 179-181 (1998); andChaperon, F., et al., “Involvement of Central Cannabinoid (CB1)Receptors in the Establishment of Place Conditioning in Rats,”Psychopharmacology, 135, 324-332 (1998). For a review of cannabinoid CB1and CB2 receptor modulators, see Pertwee, R. G., “Cannabinoid ReceptorLigands: Clinical and Neuropharmacological Considerations, Relevant toFuture Drug Discovery and Development,” Exp. Opin. Invest. Drugs, 9(7),1553-1571 (2000).

[0008] Although investigations are on-going, there still exists a needfor a more effective and safe therapeutic treatment for reducing orpreventing weight-gain.

[0009] In addition to obesity, there also exists an unmet need fortreatment of alcohol abuse. Alcoholism affects approximately 10.9million men and 4.4 million women in the United States. Approximately100,000 deaths per year have been attributed to alcohol abuse ordependence. Health risks associated with alcoholism include impairedmotor control and decision making, cancer, liver disease, birth defects,heart disease, drug/drug interactions, pancreatitis and interpersonalproblems. Studies have suggested that endogenous cannabinoid tone playsa critical role in the control of ethanol intake. The endogenous CB1receptor antagonist SR-141716A has been shown to block voluntary ethanolintake in rats and mice. See, Arnone, M., et al., “Selective Inhibitionof Sucrose and Ethanol Intake by SR141716, an Antagonist of CentralCannabinoid (CB1) Receptors,” Psychopharmacol, 132, 104-106 (1997). Fora review, see Hungund, B. L and B. S. Basavarajappa, “Are Anandamide andCannabinoid Receptors involved in Ethanol Tolerance? A Review of theEvidence,” Alcohol & Alcoholism. 35(2) 126-133, 2000.

[0010] Current treatments for alcohol abuse or dependence generallysuffer from non-compliance or potential hepatotoxicity; therefore, thereis a high unmet need for more effective treatment of alcoholabuse/dependence.

SUMMARY

[0011] The present invention provides compounds of Formula (I) that actas cannabinoid receptor ligands (in particular, CB1 receptorantagonists)

[0012] wherein

[0013] A is N or C(R²), where R² is hydrogen, (C₁-C₄)alkyl,halo-substituted (C₁-C₄)alkyl, or (C₁-C₄)alkoxy;

[0014] R⁰ is an optionally substituted heteroaryl or a substituted aryl(preferably, R⁰ is a substituted phenyl, more preferably a phenylsubstituted with one to three substituents independently selected fromthe group consisting of halo (preferably, chloro or fluoro),(C₁-C₄)alkoxy, (C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl (preferablyfluoro-substituted alkyl), and cyano, most preferably, R⁰ is2-chlorophenyl, 2-fluorophenyl, 2,4-dichlorophenyl,2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, or2,4-difluorophenyl);

[0015] R¹ is an optionally substituted heteroaryl or a substituted aryl(preferably, R¹ is a substituted phenyl, more preferably a phenylsubstituted with one to three substituents independently selected fromthe group consisting of halo (preferably, chloro or fluoro),(C₁-C₄)alkoxy, (C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl (preferablyfluoro-substituted alkyl), and cyano, most preferably, R¹ is4-chlorophenyl or 4-fluorophenyl);

[0016] R³ is hydrogen, (C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl, or(C₁-C₄)alkoxy;

[0017] R⁴ is

[0018] (i) a group having Formula (IA) or Formula (IB)

[0019]  where R^(4a) is hydrogen or (C₁-C₃)alkyl;

[0020] R^(4b) and R^(4b′) are each independently hydrogen, cyano,hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a 3-6 membered partially or fully saturated heterocycle, anda partially or fully saturated carbocyclic ring, where said moiety isoptionally substituted with one or more substituents,

[0021] or either R^(4b) or R^(4b′) taken together with R^(4e), R^(4e′),R^(4f), or R^(4f′) forms a bond, a methylene bridge, or an ethylenebridge;

[0022] X is a bond, —CH₂CH₂— or —C(R^(4c))(R^(4c′))—, where R^(4c) andR^(4c′) are each independently hydrogen, cyano, hydroxy, amino,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, ((C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a 3-6membered partially or fully saturated carbocyclic ring, where saidmoiety is optionally substituted with one or more substituents,

[0023] or either R^(4c) or R^(4c′) taken together with R^(4e), R^(4e′),R^(4f), or R^(4f′) forms a bond, a methylene bridge or an ethylenebridge;

[0024] Y is oxygen, sulfur, —C(O)—, or —C(R^(4d))(R^(4d′))-, whereR^(4d)and R^(4d′) are each independently hydrogen, cyano, hydroxy,amino, H₂NC(O)—, or a chemical moiety selected from the group consistingof (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, ((C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a 3-6membered partially or fully saturated carbocyclic ring, where saidmoiety is optionally substituted with one or more substituents,

[0025] or R^(4d) and R^(4d′) taken together form a 3-6 memberedpartially or fully saturated carbocyclic ring, 3-6 membered partially orfully saturated heterocyclic ring, a 5-6 membered lactone ring, or a 4-6membered lactam ring, where said carbocyclic ring, said heterocyclicring, said lactone ring and said lactam ring are optionally substitutedwith one or more substituents and said lactone ring and said lactam ringoptionally contain an additional heteroatom selected from oxygen,nitrogen or sulfur, or

[0026] Y is —NR^(4d″)-, where R^(4d″) is a hydrogen or a chemical moietyselected from the group consisting of (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₁-C₃)alkylsulfonyl-, (C₁-C₃)alkylaminosulfonyl-,di(C₁-C₃)alkylaminosulfonyl-, acyl, (C₁-C₆)alkyl-O—C(O)—, aryl, andheteroaryl, where said moiety is optionally substituted with one or moresubstituents;

[0027] Z is a bond, —CH₂CH₂—, or —C(R^(4e))(R^(4e′))—, where R⁴′ andR^(4e) are each independently hydrogen, cyano, hydroxy, amino, H₂NC(O)—,or a chemical moiety selected from the group consisting of (C₁-C₆)alkyl,(C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, ((C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a 3-6membered partially or fully saturated carbocyclic ring, where saidmoiety is optionally substituted with one or more substituents,

[0028] or either R^(4e) or R^(4e′) taken together with R^(4b), R^(4b′),R^(4c), or R^(4c′) forms a bond, a methylene bridge or an ethylenebridge; and

[0029] R^(4f) and R^(4f′) are each independently hydrogen, cyano,hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, ((C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a 3-6 membered partially or fully saturated heterocycle, anda 3-6 membered partially or fully saturated carbocyclic ring, where saidmoiety is optionally substituted with one or more substituents,

[0030] or either R^(4f) or R^(4f′) taken together with R^(4b), R^(4b′),R^(4c), or R^(4c′) forms a bond, a methylene bridge or an ethylenebridge;

[0031] (ii) a group having Formula (IC)

[0032] where R⁵ and R⁶ are each independently hydrogen, aryl, or(C₁-C₄)alkyl, and R⁷ is an optionally substituted (C₁-C₄)alkyl-, or anoptionally substituted 4-6 membered partially or fully saturatedheterocylic ring containing 1 to 2 heteroatoms independently selectedfrom oxygen, sulfur or nitrogen,

[0033] or R⁵ and R⁶ or R⁵ and R⁷ taken together form a 5-6 memberedlactone, 4-6 membered lactam, or a 4-6 membered partially or fullysaturated heterocycle containing 1 to 2 heteroatoms independentlyselected from oxygen, sulfur or nitrogen, where said lactone, saidlactam and said heterocycle are optionally substituted with one or moresubstituents;

[0034] (iii) an amino group having attached thereto at least onechemical moiety selected from the group consisting of (C₁-C₈)alkyl,aryl, aryl(C₁-C₄)alkyl, a 3-8 membered partially or fully saturatedcarbocyclic ring, hydroxy(C₁-C₆)alkyl, (C₁-C₃)alkoxy(C₁-C₆)alkyl,heteroaryl(C₁-C₃)alkyl, and a fully or partially saturated heterocycle,where said chemical moiety is optionally substituted with one or moresubstituents; or

[0035] (iv) an (C₁-C₆)alkyl group having attached thereto at least onechemical moiety selected from the group consisting of hydroxy,(C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino, di((C₁-C₆)alkyl)amino(C₁-C₃)alkylsulfonyl, (C₁-C₃)alkylsulfamyl, di((C₁-C₃)alkyl)sulfamyl,acyloxy, a fully or partially saturated heterocycle, and a fully orpartially saturated carbocyclic ring, where said chemical moiety isoptionally substituted with one or more substituents;

[0036] a pharmaceutically acceptable salt thereof, a prodrug of thecompound or the salt, or a solvate or hydrate of the compound, the saltor the prodrug.

[0037] In another embodiment of the present invention, a compound ofFormula (II) is provided.

[0038]  wherein

[0039] A is N or C(R²), where R² is hydrogen, (C₁-C₄)alkyl,halo-substituted (C₁-C₄)alkyl, or (C₁-C₄)alkoxy;

[0040] R^(0a), R^(0b), R^(1a), and R^(1b) are each independently halo,(C₁-C₄)alkoxy, (C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl, or cyano;

[0041] n and m are each independently 0, 1 or 2;

[0042] R³ is hydrogen, (C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl, or(C₁-C₄)alkoxy;

[0043] R⁴ is

[0044] (i) a group having Formula (IA) or Formula (IB)

[0045] where R^(4a) is hydrogen or (C₁-C₃)alkyl;

[0046] R^(4b) and R^(4b′) are each independently hydrogen, cyano,hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a 3-6 membered partially or fully saturated heterocycle, anda partially or fully saturated carbocyclic ring, where the moiety isoptionally substituted with one or more substituents,

[0047] or either R^(4b) or R^(4b′) taken together with R^(4e), R^(4e′),R^(4f), or R^(4f′) forms a bond, a methylene bridge, or an ethylenebridge;

[0048] X is a bond, —CH₂CH₂— or —C(R^(4c))(R^(4c′))-, where R^(4c) andR^(4c′) are each independently hydrogen, cyano, hydroxy, amino,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, ((C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a 3-6membered partially or fully saturated carbocyclic ring, where the moietyis optionally substituted with one or more substituents,

[0049] or either R^(4c) or R^(4c′) taken together with R^(4e), R^(4e′),R^(4f), or R^(4f′) forms a bond, a methylene bridge or an ethylenebridge;

[0050] Y is oxygen, sulfur, —C(O)—, or —C(R^(4d))(R^(4d′))-, whereR^(4d) and R^(4d′) are each independently hydrogen, cyano, hydroxy,amino, H₂NC(O)—, or a chemical moiety selected from the group consistingof (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, ((C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a 3-6membered partially or fully saturated carbocyclic ring, where the moietyis optionally substituted with one or more substituents,

[0051] or R^(4d) and R^(4d′) taken together form a 3-6 memberedpartially or fully saturated carbocyclic ring, a 3-6 membered partiallyor fully saturated heterocyclic ring, a 5-6 membered lactone ring, or a4-6 membered lactam ring, where said carbocyclic ring, said heterocyclicring, said lactone ring and said lactam ring are optionally substitutedwith one or more substituents and said lactone ring and said lactam ringoptionally contain an additional heteroatom selected from oxygen,nitrogen or sulfur, or

[0052] Y is —NR^(4d″)—, where R^(4d″) is a hydrogen or a chemical moietyselected from the group consisting of (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₁-C₃)alkylsulfonyl-, (C₁-C₃)alkylaminosulfonyl-,di(C₁-C₃)alkylaminosulfonyl-, acyl, (C₁-C₆)alkyl-O—C(O)—, aryl, andheteroaryl, where the moiety is optionally substituted with one or moresubstituents;

[0053] Z is a bond, —CH₂CH₂—, or —C(R^(4e))(R^(4e′))—, where R^(4e) andR^(4e′) are each independently hydrogen, cyano, hydroxy, amino,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, ((C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocyclic ring, and a 3-6membered partially or fully saturated carbocyclic ring, where the moietyis optionally substituted with one or more substituents,

[0054] or either R^(4e) or R^(4e′) taken together with R^(4b), R^(4b′),R^(4c), or R^(4c′) forms a bond, a methylene bridge or an ethylenebridge; and

[0055] R^(4f) and R^(4f′) are each independently hydrogen, cyano,hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, ((C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a 3-6 membered partially or fully saturated heterocycle, anda 3-6 membered partially or fully saturated carbocyclic ring, where themoiety is optionally substituted with one or more substituents,

[0056] or either R^(4f) or R^(4f′) taken together with R^(4b), R^(4b′),R^(4c), or R^(4c′) forms a bond, a methylene bridge or an ethylenebridge;

[0057] (ii) a group having Formula (IC)

[0058] where R⁵ and R⁶ are each independently hydrogen, aryl, or(C₁-C₄)alkyl, and R⁷ is an optionally substituted (C₁-C₄)alkyl-, or anoptionally substituted 4-6 membered partially or fully saturatedheterocylic ring containing 1 to 2 heteroatoms independently selectedfrom oxygen, sulfur or nitrogen,

[0059] or R⁵ and R⁶ or R⁵ and R⁷ taken together form a 5-6 memberedlactone, 4-6 membered lactam, or a 4-6 membered partially or fullysaturated heterocycle containing 1 to 2 heteroatoms independentlyselected from oxygen, sulfur or nitrogen, where said lactone, saidlactam and said heterocycle are optionally substituted with one or moresubstituents;

[0060] (iii) an amino group having attached thereto at least onechemical moiety selected from the group consisting of (C₁-C₈)alkyl,aryl, aryl(C₁-C₄)alkyl, a 3-8 membered partially or fully saturatedcarbocyclic ring, hydroxy(C₁-C₆)alkyl, (C₁-C₃)alkoxy(C₁-C₆)alkyl,heteroaryl(C₁-C₃)alkyl, and a fully or partially saturated heterocycle,where said chemical moiety is optionally substituted with one or moresubstituents; or

[0061] (iv) an (C₁-C₆)alkyl group having attached thereto at least onechemical moiety selected from the group consisting of hydroxy,(C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino,di((C₁-C₆)alkyl)amino(C₁-C₃)alkylsulfonyl, (C₁-C₃)alkylsulfamyl,di((C₁-C₃)alkyl)sulfamyl, acyloxy, a fully or partially saturatedheterocycle, and a fully or partially saturated carbocyclic ring, wheresaid chemical moiety is optionally substituted with one or moresubstituents;

[0062] a pharmaceutically acceptable salt thereof, a prodrug of thecompound or the salt, or a solvate or hydrate of the compound, the saltor the prodrug.

[0063] A preferred compound of the present invention is a compound ofFormula (I) or (II) where R⁴ is a group of Formula (IA). Preferably,R^(4b) and R^(4b) are each independently hydrogen, H₂NC(O)—, or achemical moiety selected from the group consisting of (C₁-C₆)alkyl,acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a partially or fully saturated3-6 membered heterocycle, and a partially or fully saturated carbocyclicring, where the moiety is optionally substituted, or R^(4b) or R^(4b′)taken together with R^(4e), R^(4e′), R^(4f), or R^(4f′) forms a bond, amethylene bridge, or an ethylene bridge;

[0064] X is a bond, —CH₂CH₂— or —C(R^(4c))(R^(4c′))—, where R^(4c) ishydrogen, cyano, hydroxy, amino, H₂NC(O)—, or a chemical moiety selectedfrom the group consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a partially or fully saturated 3-6 membered heterocycle, anda partially or fully saturated carbocyclic ring, where the moiety isoptionally substituted, or R^(4c) taken together with R^(4e), R^(4e′),R^(4f), or R^(4′) forms a bond, a methylene bridge, or an ethylenebridge, and R^(4c′) is hydrogen, H₂NC(O)—, or a chemical moiety selectedfrom the group consisting of (C₁-C₆)alkyl acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, apartially or fully saturated 3-6 membered heterocycle, and a partiallyor fully saturated carbocyclic ring, where the moiety is optionallysubstituted, or R^(4c′) taken together with R^(4e), R^(4e′), R^(4f), orR⁴° forms a bond, a methylene bridge, or an ethylene bridge;

[0065] Y is oxygen, sulfur, —C(O)—, or —C(R^(4d))(R^(4d′))—, whereR^(4d) is hydrogen, cyano, hydroxy, amino, H₂NC(O)—, or a chemicalmoiety selected from the group consisting of (C₁-C₆)alkyl,(C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a partially or fully saturated 3-6 membered heterocycle, and a partiallyor fully saturated carbocyclic ring, where the moiety is optionallysubstituted, and R^(4d′) is hydrogen, H₂NC(O)—, or a chemical moietyselected from the group consisting of (C₁-C₆)alkyl, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,aryl, heteroaryl, a partially or fully saturated 3-6 memberedheterocycle, and a partially or fully saturated carbocyclic ring, wherethe moiety is optionally substituted, or R^(4d) and R^(4d′) takentogether form a partially or fully saturated, 3-6 membered heterocyclicring, a 5-6 membered lactone ring, or a 4-6 membered lactam ring, wherethe heterocyclic ring, the lactone ring and the lactam ring areoptionally substituted and the lactone ring and the lactam ringoptionally contain an additional heteroatom selected from oxygen,nitrogen or sulfur, or

[0066] Y is —NR^(4d)—, where R^(4d) is a hydrogen or a chemical moietyselected from the group consisting of (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₁-C₃)alkylsulfonyl-, (C₁-C₃)alkylaminosulfonyl-,di(C₁-C₃)alkylaminosulfonyl-, acyl, (C₁-C₆)alkyl-O—C(O)—, aryl, andheteroaryl, where the moiety is optionally substituted;

[0067] Z is a bond, —CH₂CH₂—, or —C(R^(4e))(R^(4e′))—, where R^(4e) ishydrogen, cyano, hydroxy, amino, H₂NC(O)—, or a chemical moiety selectedfrom the group consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a partially or fully saturated 3-6 membered heterocycle, anda partially or fully saturated carbocyclic ring, where the moiety isoptionally substituted, or R^(4e) taken together with R^(4b), R^(4b′),R^(4c), or R^(4c′) forms a bond, a methylene bridge, or an ethylenebridge, and R^(4e′) is hydrogen, H₂NC(O)—, or a chemical moiety selectedfrom the group consisting of (C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, apartially or fully saturated 3-6 membered heterocycle, and a partiallyor fully saturated carbocyclic ring, where the moiety is optionallysubstituted, or R^(4e′) taken together with R^(4b), R^(4b′), R^(4c), orR^(4c′) forms a bond, a methylene bridge, or an ethylene bridge; and

[0068] R^(4f) and R^(4f′) are each independently hydrogen, H₂NC(O)—, ora chemical moiety selected from the group consisting of (C₁-C₆)alkyl,acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a partially or fully saturated3-6 membered heterocycle, and a partially or fully saturated carbocyclicring, where the moiety is optionally substituted, or R^(4f) or R^(4f′)taken together with R^(4b), R^(4b′), R^(4c), or R^(4c′) forms a bond, amethylene bridge, or an ethylene bridge;

[0069] a pharmaceutically acceptable salt thereof, a prodrug of thecompound or the salt, or a solvate or hydrate of the compound, the saltor the prodrug.

[0070] Preferably, R^(4b) is hydrogen, an optionally substituted(C₁-C₃)alkyl, or taken together with R^(4e), R^(4e′), R^(4f), or R^(4f′)forms a bond, a methylene bridge, or an ethylene bridge; R^(4b′) ishydrogen, an optionally substituted (C₁-C₃)alkyl, or taken together withR^(4e), R^(4e′), R^(4f), or R^(4f′)forms a bond, a methylene bridge, oran ethylene bridge; R^(4f) is hydrogen, an optionally substituted(C₁-C₃)alkyl, or taken together with R^(4b), R^(4b′), R^(4c), or R^(4c′)forms a bond, a methylene bridge, or an ethylene bridge; and R^(4f) ishydrogen, an optionally substituted (C₁-C₃)alkyl, or taken together withR^(4b), R^(4b′), R^(4c), or R^(4c′) forms a bond, a methylene bridge, oran ethylene bridge, and even more preferably, R^(4b), R^(4b′), R^(4f),and R^(4f′) are all hydrogen.

[0071] When Y is —NR^(4d″)—, then R^(4d″) is preferably a hydrogen or achemical moiety selected from the group consisting of (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₁-C₃)alkylsulfonyl, (C₁-C₃)alkylaminosulfonyl,di(C₁-C₃)alkylaminosulfonyl, acyl, (C₁-C₆)alkyl-O—C(O)—, aryl, andheteroaryl, where the moiety is optionally substituted (more preferably,R^(4d″) is a hydrogen or a chemical moiety selected from the groupconsisting of (C₁-C₃)alkylsulfonyl, (C₁-C₃)alkylaminosulfonyl,di(C₁-C₃)alkylaminosulfonyl, acyl, (C₁-C₆)alkyl-O—C(O)—, and heteroaryl,where the moiety is optionally substituted (preferably the(C₁-C₃)alkylsulfonyl, (C₁-C₃)alkylaminosulfonyl,di(C₁-C₃)alkylaminosulfonyl, acyl, and (C₁-C₆)alkyl-O—C(O)— areoptionally substituted with 1-3 fluorines, and the heteroaryl isoptionally substituted with 1 to 2 substituents independently selectedfrom the group consisting of chloro, fluoro, (C₁-C₃)alkoxy,(C₁-C₃)alkyl, and fluoro-substituted (C₁-C₃)alkyl);

[0072] X is —C(R^(4c))(R^(4c′))—, where R^(4c) and R^(4c′) are eachindependently hydrogen, H₂NC(O)—, an optionally substituted(C₁-C₆)alkyl, (C₁-C₄)alkyl-NH—C(O)—, or ((C₁-C₄)alkyl)₂N—C(O)—, oreither R^(4c) or R^(4c′) taken together with R^(4e), R^(4e′), R^(4f), orR^(4f′) forms a bond, a methylene bridge or an ethylene bridge; and

[0073] Z is —C(R^(4e))(R^(4e′))-, where R^(4e) and R^(4e′) are eachindependently hydrogen, H₂NC(O)—, an optionally substituted(C₁-C₆)alkyl, (C₁-C₄)alkyl-NH—C(O)—, or ((C₁-C₄)alkyl)₂N—C(O)—, oreither R^(4e) or R^(4e′) taken together with R^(4b), R^(4b′), R^(4c), orR^(4c′) forms a bond, a methylene bridge or an ethylene bridge.

[0074] When Y is —C(R^(4d))(R^(4d′))—, then R^(4d) is hydrogen, cyano,hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a partially or fully saturated 3-6 membered heterocycle, anda partially or fully saturated carbocyclic ring, where the moiety isoptionally substituted (preferably, R^(4d) is amino, (C₁-C₆)alkylamino,di(C₁-C₄)alkylamino, (C₃-C₆)cycloalkylamino, acylamino,aryl(C₁-C₄)alkylamino-, or heteroaryl(C₁-C₄)alkylamino, more preferably,R^(4d) is amino, (C₁-C₆)alkylamino, di(C₁-C₄)alkylamino,(C₃-C₆)cycloalkylamino), and

[0075] R^(4d′) is hydrogen, H₂NC(O)—, or a chemical moiety selected fromthe group consisting of (C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, apartially or fully saturated 3-6 membered heterocycle, and a partiallyor fully saturated carbocyclic ring, where the moiety is optionallysubstituted (preferably, R^(4d′) is (C₁-C₆)alkyl, H₂NC(O)—,(C₁-C₄)alkyl-NH—C(O)—, or ((C₁-C₄)alkyl)₂N—C(O)—, or aryl, morepreferably, R^(4d′) is H₂NC(O)—, (C₁-C₄)alkyl-NH—C(O)—, or((C₁-C₄)alkyl)₂N—C(O)—),

[0076] or R^(4d) and R^(4d′) taken together form a partially or fullysaturated, 3-6 membered heterocyclic ring, a 5-6 membered lactone ring,or a 4-6 membered lactam ring, where the heterocyclic ring, the lactonering and the lactam ring are optionally substituted and the lactone ringand the lactam ring optionally contain an additional heteroatom selectedfrom oxygen, nitrogen or sulfur;

[0077] X is a bond or —C(R^(4c))(R^(4c′))—, where R^(4c) and R^(4c′) areeach hydrogen; and Z is a bond or —C(R^(4e))(R^(4e′))—, where R^(4e) andR^(4e′) are each hydrogen.

[0078] Preferred compounds include:3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-7-(4-methylpiperazin-1-yl)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(5-cyclopentyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2H-pyrazolo[4,3-d]pyrimidine;5-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester; 5-[3-(4-diazabicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(5-methanesulfonyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-[5-(propane-2-sulfonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2H-pyrazolo[4,3-d]pyrimidine;3-(4-diazabicyclo[2.2.1]hept-2-yl]-2H-pyrazolo[4,3-d]pyrimidine;5-[3-(4-chlorophenyl)-2-2-sulfonic acid dimethylamide;4-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-piperazine-1-sulfonicacid dimethylamide;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(4-ethanesulfonylpiperazin-1-yl)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(4-(2,2,2-trifluoroethane)sulfonylpiperazin-1-yl)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(4-methanesulfonylpiperazin-1-yl)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(4-(propane-2-sulfonyl)piperazin-1-yl)-2H-pyrazolo[4,3-d]pyrimidine;and 3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-7-(4-methylpiperazin-1-yl)-2H-pyrazolo[3,4-c]pyridine; a pharmaceutically acceptable saltthereof, or a solvate or hydrate of said compound or said salt.

[0079] In another preferred embodiment, a compound of Formula (I) or(II) is provided where Y is —C(R^(4d))(R^(4d′))—, R^(4b), R^(4b′),R^(4f), and R^(4f′) are all hydrogen; R^(4d) is hydrogen, cyano,hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a 3-6 membered partially or fully saturated heterocycle, anda partially or fully saturated carbocyclic ring, where said moiety isoptionally substituted with one or more substituents; and R^(4d′) ishydrogen, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6membered partially or fully saturated heterocycle, and a partially orfully saturated carbocyclic ring, where said moiety is optionallysubstituted with one or more substituents.

[0080] In this embodiment, X is preferably —C(R^(4c))(R^(4c′))—, whereR^(4c) and R^(4c′) are each independently hydrogen or an optionallysubstituted (C₁-C₆)alkyl, or either R^(4c) or R^(4c′) taken togetherwith R^(4e) or R^(4e′), forms a bond, a methylene bridge or an ethylenebridge (preferably, R⁴ and R^(4c′) are each hydrogen or either R^(4c) orR^(4c′) taken together with R^(4e) or R^(43′) forms a bond); and Z ispreferably —C(R^(4e))(R^(4e′))—, where R^(4e), and R^(4e′) are eachindependently hydrogen or an optionally substituted (C₁-C₆)alkyl, oreither R^(4e) or R^(4e′) taken together with R^(4c) or R^(4c′) forms abond, a methylene bridge or an ethylene bridge (preferably, R^(4e) andR^(4e′) are each hydrogen or either R^(4e) or R^(4e′) taken togetherwith R⁴C or R^(4c′) forms a bond). Preferably, R^(4d) is amino,(C₁-C₆)alkylamino, di(C₁-C₄)alkylamino, azetidinyl, piperidinyl,pyrrolidinyl, morpholinyl, (C₃-C₆)cycloalkylamino, acylamino,aryl(C₁-C₄)alkylamino-, or heteroaryl(C₁-C₄)alkylamino-; and R^(4d′) is(C₁-C₆)alkyl, H₂NC(O)—, (C₁-C₄)alkyl-NH—C(O)—, ((C₁-C₄)alkyl)₂N—C(O)—,or aryl. More preferably, R^(4d) is amino, (C₁-C₆)alkylamino,di(C₁-C₄)alkylamino, (C₃-C₆)cycloalkylamino, piperidinyl, pyrrolidinyl,or morpholinyl; and R^(4d′) is H₂NC(O)—, (C₁-C₄)alkyl-NH—C(O)—, or((C₁-C₄)alkyl)₂N—C(O)—.

[0081] In yet another preferred embodiment, a compound of Formula (I) or(II) is provided where Y is C(R^(4d))(R^(4d′)), R^(4b), R^(4b′), R^(4f),and R^(4f′) are all hydrogen; and R^(4d) and R^(4d′) taken together forma partially or fully saturated 3-6 membered heterocyclic ring, a 5-6membered lactone ring, or a 4-6 membered lactam ring, where theheterocyclic ring, the lactone ring and the lactam ring are optionallysubstituted with one or more substituents and the lactone ring or thelactam ring optionally contains an additional heteroatom selected fromoxygen, nitrogen or sulfur (preferably, R^(4d) and R^(4d′) takentogether form a 5-6 membered lactam ring, where the lactam ring isoptionally substituted and optionally contains an additional heteroatomselected from nitrogen or oxygen). In this embodiment, X is preferably abond, —CH₂CH₂— or —C(R^(4c))(R^(4c′))—, where R^(4c) and R^(4c′) areeach independently hydrogen or an optionally substituted (C₁-C₆)alkyl,or either R^(4c) or R^(4c′) taken together with R^(4e) or R^(4e′) formsa bond, a methylene bridge or an ethylene bridge (more preferably, X isa bond or —C(R^(4c))(R^(4c′))—, where R^(4c) and R^(4c′) are eachhydrogen); and Z is preferably a bond, —CH₂CH₂— or

[0082] —C(R^(4e))(R^(4e′))—, where R^(4e) and R^(4e′) are eachindependently hydrogen or an optionally substituted (C₁-C₆)alkyl, oreither R^(4e) or R^(4e′) taken together with R^(4c) or R^(4c′) forms abond, a methylene bridge or an ethylene bridge (more preferably, Z is abond or —C(R^(4e))(R^(4e′))—, where R^(4e) and R^(4e′) are eachhydrogen).

[0083] Preferred compounds include:1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-ethylaminoazetidine-3-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-methylaminoazetidine-3-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-(2-propylamino)azetidine-3-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-isopropylaminopiperidine-4-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-ethylaminopiperidine-4-carboxylicacid amide;1′-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-[1,4′]bipiperidinyl-4′-carboxylicacid amide;8-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-pyrrolidin-1-yl-8-aza-bicyclo[3.2.1]octane-3-carboxylicacid amide;1′-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-[1,3′]bipyrrolidinyl-3′-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-morpholin-4-yl-pyrrolidine-3-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-isopropylaminopyrrolidine-3-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[3,4-c]pyridin-7-yl]-4-isopropylaminopiperidine-4-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[3,4-c]pyridin-7-yl]4-ethylaminopiperidine-4-carboxylicacid amide; and1′-[3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[3,4-c]pyridin-7-yl]-[1,4′]bipiperidinyl-4′-carboxylicacid amide a pharmaceutically acceptable salt thereof or a solvate orhydrate of said compound or said salt.

[0084] More preferred compounds include:1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]4-isopropylaminopiperidine-4-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]4-ethylaminopiperidine-4-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-isopropylaminopyrrolidine-3-carboxylicacid amide; and1′-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-[1,4′]bipiperidinyl-4′-carboxylicacid amide; a pharmaceutically acceptable salt thereof or a solvate orhydrate of said compound or said salt.

[0085] Another set of preferred compounds include:1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-phenylpiperidin-4-ol;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]4-ethylpiperidin-4-ol;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-isopropylpiperidin-4-ol;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-sec-butylpiperidin-4-ol;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-methylpiperidin-4-ol;8-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-ethyl-8-azabicyclo[3.2.1]octan-3-ol;8-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-sec-butyl-8-azabicyclo[3.2.1]octan-3-ol;8-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-isopropyl-8-azabicyclo[3.2.1]octan-3-ol;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-isobutyl-pyrrolidin-3-ol;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-isopropyl-pyrrolidin-3-ol;{8-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-8-aza-bicyclo[3.2.1]oct-3-yl}-ethyl-amine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(3-pyrrolidin-1-yl-8-aza-bicyclo[3.2.1]oct-8-yl)-2H-pyrazolo[4,3-d]pyrimidine;7-(3-bromo-8-azabicyclo[3.2.1]oct-8-yl)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine;7-(3-bromo-8-azabicyclo[3.2.1]oct-8-yl)-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(4-methylpiperidin-1-yl)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(3-hydroxypiperidin-1-yl)-2H-pyrazolo[4,3-d]pyrimidine;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-(3-methoxyphenyl)-piperidine-4-carbonitrile;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-phenylpiperidine-4-carbonitrile;1-{1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-phenylpiperidin-4-yl}-propan-1-one;1′-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-2′,3′,5′,6′-tetrahydro-1′H-[3,4′]bipyridinyl-4′-carbonitrile;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-2,3,5,6-tetrahydro-1H-[4,4′]bipyridinyl-4-carbonitrile;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-2,3,5,6-tetrahydro-1H-[2,4′]bipyridinyl-4-carbonitrile;{1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]4-phenylpiperidin-4-yl}-morpholin-4-yl-methanone;benzyl-{8-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-8-aza-bicyclo[3.2.1]oct-3-yl}-amine;{1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-pyrrolidin-3-yl}-methylcarbamicacid tert-butyl ester;{1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-pyrrolidin-3-yl}-carbamicacid tert-butyl ester;N-{1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-pyrrolidin-3-yl}-N-methylacetamide;and{1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-pyrrolidin-3-yl}-dimethylamine;a pharmaceutically acceptable salt thereof, or a solvate or hydrate ofsaid compound or said salt.

[0086] Yet another set of preferred compounds include:2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-5-methyl-2,5,7-triaza-spiro[3.4]octan-8-one;8-[3-(4-chloro-phenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-1-isopropyl-1,3,8-triaza-spiro[4.5]decan-4-one;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2H-pyrazolo[4,3-d]pyrimidine;3-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-1-spiro[(5-methoxy)tetrahydronaphthalene-1,4′-piperidine];3-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-1-spiro[(6-methoxy)tetrahydronaphthalene-1,4′-piperidine];and3-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-1-spiro[indane-1,4′-piperidine];a pharmaceutically acceptable salt thereof or a solvate or hydrate ofsaid compound or said salt.

[0087] Another preferred compound of the present invention is a compoundof Formula (I) or (II) where R⁴ is a group of Formula (IB) where whereR^(4a) is as defined above, R^(4b) is hydrogen, cyano, hydroxy, amino,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a partially or fully saturated 3-6 membered heterocycle, and a partiallyor fully saturated carbocyclic ring, where the moiety is optionallysubstituted with one or more substituents,

[0088] R^(4b′) is hydrogen, H₂NC(O)—, or a chemical moiety selected fromthe group consisting of (C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, apartially or fully saturated 3-6 membered heterocycle, and a partiallyor fully saturated carbocyclic ring, where the moiety is optionallysubstituted with one or more substituents,

[0089] or R^(4b) or R^(4b′) taken together with R^(4e), R^(4e′), R^(4f),or R^(4f)° forms a bond, a methylene bridge, or an ethylene bridge;

[0090] X is a bond, —CH₂CH₂— or —C(R^(4c))(R^(4c′))—, where R^(4c) ishydrogen, cyano, hydroxy, amino, H₂NC(O)—, or a chemical moiety selectedfrom the group consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a partially or fully saturated 3-6 membered heterocycle, anda partially or fully saturated carbocyclic ring, where the moiety isoptionally substituted with one or more substituents, or R^(4c) takentogether with R^(4e), R^(4e′), R^(4f), or R^(4f′) forms a bond, amethylene bridge, or an ethylene bridge, and R^(4c′) is hydrogen,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a partially or fully saturated3-6 membered heterocycle, and a partially or fully saturated carbocyclicring, where the moiety is optionally substituted with one or moresubstituents, or R^(4c′) taken together with R^(4e), R^(4e′), R^(4f), orR^(4f′) forms a bond, a methylene bridge, or an ethylene bridge(preferably, X is a bond, —CH₂CH₂— or —C(R^(4c))(R^(4c′))—, where R^(4c)and R^(4c′) are each independently hydrogen or (C₁-C₆)alkyl);

[0091] Y is oxygen, sulfur, —C(O)—, or —C(R^(4d))(R^(4d′))—, whereR^(4d) is hydrogen, cyano, hydroxy, amino, H₂NC(O)—, or a chemicalmoiety selected from the group consisting of (C₁-C₆)alkyl,(C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a partially or fully saturated 3-6 membered heterocycle, and a partiallyor fully saturated carbocyclic ring, where the moiety is optionallysubstituted with one or more substituents, and R^(4d′) is hydrogen,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a partially or fully saturated3-6 membered heterocycle, and a partially or fully saturated carbocyclicring, where the moiety is optionally substituted with one or moresubstituents, or R^(4d) and R^(4d′) taken together form a partially orfully saturated, 3-6 membered heterocyclic ring, a 5-6 membered lactonering, or a 4-6 membered lactam ring, where the heterocyclic ring, thelactone ring and the lactam ring are optionally substituted with one ormore substituents and the lactone ring and the lactam ring optionallycontain an additional heteroatom selected from oxygen, nitrogen orsulfur, or

[0092] Y is —NR^(4d″)—, where R^(4d″) is a hydrogen or a chemical moietyselected from the group consisting of (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₁-C₃)alkylsulfonyl-, (C₁-C₃)alkylaminosulfonyl-,di(C₁-C₃)alkylaminosulfonyl-, acyl, (C₁-C₆)alkyl-O—C(O)—, aryl, andheteroaryl, where the moiety is optionally substituted with one or moresubstituents (preferably, Y is —NR^(4d″)—, where R^(4d″) is a hydrogenor a chemical moiety selected from the group consisting of (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₁-C₃)alkylsulfonyl-, (C₁-C₃)alkylaminosulfonyl-,di(C₁-C₃)alkylaminosulfonyl-, acyl, (C₁-C₆)alkyl-O—C(O)—, aryl, andheteroaryl, where the moiety is optionally substituted with one or moresubstituents);

[0093] Z is a bond, —CH₂CH₂—, or —C(R^(4e))(R^(4e′))-, where R^(4e) ishydrogen, cyano, hydroxy, amino, H₂NC(O)—, or a chemical moiety selectedfrom the group consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a partially or fully saturated 3-6 membered heterocycle, anda partially or fully saturated carbocyclic ring, where the moiety isoptionally substituted with one or more substituents, or R^(4e) takentogether with R^(4b), R^(4b′), R^(4c), or R^(4c′) forms a bond, amethylene bridge, or an ethylene bridge, and R^(4e′) is hydrogen,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a partially or fully saturated3-6 membered heterocycle, and a partially or fully saturated carbocyclicring, where the moiety is optionally substituted with one or moresubstituents, or R^(4e′) taken together with R^(4b), R^(4b′), R^(4c), orR^(4c′) forms a bond, a methylene bridge, or an ethylene bridge(preferably, Z is a bond, —CH₂CH₂— or —C(R^(4c))(R^(4c′))—, where R^(4c)and R^(4c′) are each independently hydrogen or (C₁-C₆)alkyl);

[0094] R^(4f) is hydrogen, cyano, hydroxy, amino, H₂NC(O)—, or achemical moiety selected from the group consisting of (C₁-C₆)alkyl,(C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a partially or fully saturated 3-6 membered heterocycle, and a partiallyor fully saturated carbocyclic ring, where the moiety is optionallysubstituted with one or more substituents; and

[0095] R^(4f) is hydrogen, H₂NC(O)—, or a chemical moiety selected fromthe group consisting of (C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, apartially or fully saturated 3-6 membered heterocycle, and a partiallyor fully saturated carbocyclic ring, where the moiety is optionallysubstituted with one or more substituents,

[0096] or R^(4f) or R^(4f′) taken together with R^(4b), R^(4b′), R^(4c),or R^(4c′) forms a bond, a methylene bridge, or an ethylene bridge;

[0097] a pharmaceutically acceptable salt thereof, a prodrug of thecompound or the salt, or a solvate or hydrate of the compound, the saltor the prodrug.

[0098] Preferred compounds include:7-(1-benzhydrylazetidin-3-yloxy)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine;and7-(1-benzylpyrrolidin-3-yloxy)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine;a pharmaceutically acceptable salt thereof or a solvate or hydrate ofsaid compound or said salt.

[0099] Yet another preferred compound of the present invention is acompound of Formula (I) or (II) where R⁴ is a group of Formula (IC),where where R⁵ and R⁶ are each independently hydrogen, aryl, or(C₁-C₄)alkyl, and R⁷ is an optionally substituted (C₁-C₄)alkyl-, or anoptionally substituted 4-6 membered partially or fully saturatedheterocylic ring containing 1 to 2 heteroatoms independently selectedfrom oxygen, sulfur or nitrogen, or R⁵ and R⁶ or R⁵ and R⁷ takentogether form a 5-6 membered lactone, 4-6 membered lactam, or a 4-6membered partially or fully saturated heterocycle containing 1 to 2heteroatoms independently selected from oxygen, sulfur or nitrogen,where said lactone, said lactam and said heterocycle are optionallysubstituted with one or more substituents; a pharmaceutically acceptablesalt thereof, or a solvate or hydrate of said compound or said salt.

[0100] Preferred compounds include:2-(2-chlorophenyl)-7-isopropoxy-3-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-d]pyrimidine;2-(2-chloro-4-methylphenyl)-5-methyl-7-(2,2,2-trifluoroethoxy)-3-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-d]pyrimidine;2-(2-chlorophenyl)-3-(4-methoxyphenyl)-5-methyl-7-(2,2,2-trifluoroethoxy)-2H-pyrazolo[4,3-d]pyrimidine;2-(2-bromophenyl)-3-(4-chlorophenyl)-7-(2,2-difluoropropoxy)-5-methyl-2H-pyrazolo[4,3-d]pyrimidine;2-(2-bromophenyl)-3-(4-methoxyphenyl)-5-methyl-7-(2,2,2-trifluoroethoxy)-2H-pyrazolo[4,3-d]pyrimidine;2-[3-(4-chlorophenyl)-7-(2,2-difluoropropoxy)-5-methylpyrazolo[4,3-d]pyrimidin-2-yl]-benzonitrile;2-(2-bromophenyl)-7-(2,2-difluoropropoxy)-3-(4-methoxyphenyl)-5-methyl-2H-pyrazolo[4,3-d]pyrimidine;3-(4-bromophenyl)-2-(2-chlorophenyl)-7-(2,2-difluoropropoxy)-5-methyl-2H-pyrazolo[4,3-d]pyrimidine;2-(2-chlorophenyl)-7-(2,2-difluoropropoxy)-3-(4-methoxyphenyl)-5-methyl-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-isopropoxy-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(2,2,2-trifluoroethoxy)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-methoxy-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-ethoxy-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-propoxy-2H-pyrazolo[4,3-d]pyrimidine;7-butoxy-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-5-ethyl-7-(2,2,2-trifluoroethoxy)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-5-isopropyl-7-(2,2,2-trifluoroethoxy)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-ethoxy-5-trifluoromethyl-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(2,2,2-trifluoroethoxy)-5-trifluoromethyl-2H-pyrazolo[4,3-d]pyrimidine;and3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(2,2-difluorobutoxy)-5-methyl-2H-pyrazolo[4,3-d]pyrimidine;

[0101] a pharmaceutically acceptable salt thereof or a solvate orhydrate of said compound or said salt.

[0102] Yet another preferred compound of the present invention is acompound of Formula (I) or (II) wherein R⁴ is an amino group havingattached thereto at least one chemical moiety selected from the groupconsisting of (C₁-C₈)alkyl, aryl, aryl(C₁-C₄)alkyl, a 3-8 memberedpartially or fully saturated carbocyclic ring, hydroxy(C₁-C₆)alkyl,(C₁-C₃)alkoxy(C₁-C₆)alkyl, heteroaryl(C₁-C₃)alkyl, and a fully orpartially saturated heterocycle, where said chemical moiety isoptionally substituted with one or more substituents.

[0103] Preferred compounds include:N-4-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-N,N-diethylpentane-1,4-diamine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(1-methyl-2-morpholin-4-yl-ethyl)-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-pyridin-2-yl-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(5-methylpyridin-2-yl)-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(5-methoxypyridin-2-yl)-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-amine;(6-azetidin-1-yl-pyridin-3-yl)-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-pyridin-2-ylmethylamine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(5-methyl-pyridin-2-ylmethyl)-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-pyridin-3-ylmethylamine;[3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-diethylamine;bicyclo[2.2.1]hept-2-yl-[3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-cyclohexylamine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-diethylamine;bicyclo[2.2.1]hept-2-yl-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(4-methyl-cyclohexyl)amine;adamantan-2-yl-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(3-methylcyclohexyl)amine;2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]cyclopentanecarboxylicacid ethyl ester;2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]cyclopentanol;2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]cyclohexanol;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(2,6-dimethylcyclohexyl)amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]cycloheptylamine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]cyclobutylamine;2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]-2-methylpropane-1,3-diol;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(1-methyl-1-phenylethyl)amine;{1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]cyclopentyl}methanol;2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]-2-methylpropan-1-ol;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(1,1-dimethylpropyl)amine;2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]-3-phenylpropan-1-ol;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-indan-2-ylamine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(1,2,3,4-tetrahydronaphthalen-1-yl)amine;2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]-1-pyrrolidin-1-ylpropan-1-one;4-{2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]propyl}phenol;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(1-cyclohexylethyl)amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(1-p-tolylethyl)amine;(3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(2-phenylcyclopropyl)amine;2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]indan-1-ol;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(2-morpholin-4-yl-ethyl)amine;(1H-Benzoimidazol-2-ylmethyl)-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-amine;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]propan-2-ol;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(2,2,2-trifluoroethyl)amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-cyclopropylmethylamine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(1-cyclohexylethyl)amine;and3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-7-pyrrolidin-1-yl-2H-pyrazolo[3,4-c]pyridine;a pharmaceutically acceptable salt thereof or a solvate or hydrate ofsaid compound or said salt.

[0104] More preferred compounds include:[3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-diethylamine;bicyclo[2.2.1]hept-2-yl-[3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-diethylamine;bicyclo[2.2.1]hept-2-yl-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-cyclohexylamine;adamantan-2-yl-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-amine;2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]cyclohexanol;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]cyclobutylamine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(1-methyl-1-phenylethyl)amine;{1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]cyclopentyl}methanol;2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]-3-phenylpropan-1-ol;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-indan-2-ylamine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(1-cyclohexylethyl)amine;and2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]indan-1-ol;a pharmaceutically acceptable salt thereof or a solvate or hydrate ofsaid compound or said salt.

[0105] Another aspect of the present invention comprises the followingintermediates which may be used in the preparation of the compounds ofFormula (I) and (II).

[0106] wherein R⁰, R¹, R², R³ are as defined above; R is an alkyl group(preferably, a (C₁-C₄)alkyl, more preferably, an ethyl); Pg is anamino-protecting group; and L is a leaving group.

[0107] Some of the compounds described herein contain at least onechiral center; consequently, those skilled in the art will appreciatethat all stereoisomers (e.g., enantiomers and diasteroisomers) of thecompounds illustrated and discussed herein are within the scope of thepresent invention. In addition, tautomeric forms of the compounds arealso within the scope of the present invention. Those skilled in the artwill recognize that chemical moieties such as an alpha-amino ether or analpha-chloro amine may be too unstable to isolate; therefore, suchmoieties do not form a part of this invention.

[0108] Compounds of the present invention have been shown to be usefulcannabinoid receptor ligands (in particular, CB1 receptor antagonists).Accordingly, another aspect of the present invention is a pharmaceuticalcomposition that comprises (1) a compound of the present invention, and(2) a pharmaceutically acceptable excipient, diluent, or carrier.Preferably, the composition comprises a therapeutically effective amountof a compound of the present invention. The composition may also containat least one additional pharmaceutical agent (described herein).Preferred agents include nicotine receptor partial agonists, opioidantagonists (e.g., naltrexone and nalmefene), dopaminergic agents (e.g.,apomorphine), attention deficit disorder (ADD including attentiondeficit hyperactivity disorder (ADHD)) agents (e.g., Ritalin™,Strattera™, Concerta™ and Adderall™), and anti-obesity agents (describedherein below).

[0109] In yet another embodiment of the present invention, a method fortreating a disease, condition or disorder modulated by a cannabinoidreceptor (preferably, a CB1 receptor) antagonists in animals thatincludes the step of administering to an animal in need of suchtreatment a therapeutically effective amount of a compound of thepresent invention (or a pharmaceutical composition thereof).

[0110] Diseases, conditions, and/or disorders modulated by cannabinoidreceptor antagonists include eating disorders (e.g., binge eatingdisorder, anorexia, and bulimia), weight loss or control (e.g.,reduction in calorie or food intake, and/or appetite suppression),obesity, depression, atypical depression, bipolar disorders, psychoses,schizophrenia, behavioral addictions, suppression of reward-relatedbehaviors (e.g., conditioned place avoidance, such as suppression ofcocaine- and morphine-induced conditioned place preference), substanceabuse, addictive disorders, impulsivity, alcoholism (e.g., alcoholabuse, addiction and/or dependence including treatment for abstinence,craving reduction and relapse prevention of alcohol intake), tobaccoabuse (e.g., smoking addiction, cessation and/or dependence includingtreatment for craving reduction and relapse prevention of tobaccosmoking), dementia (including memory loss, Alzheimer's disease, dementiaof aging, vascular dementia, mild cognitive impairment, age-relatedcognitive decline, and mild neurocognitive disorder), sexual dysfunctionin males (e.g., erectile difficulty), seizure disorders, epilepsy,inflammation, gastrointestinal disorders (e.g., dysfunction ofgastrointestinal motility or intestinal propulsion), attention deficitdisorder (ADD/ADHD), Parkinson's disease, and type II diabetes. In apreferred embodiment, the method is used in the treatment of weightloss, obesity, bulimia, ADD/ADHD, Parkinson's disease, dementia,alcoholism, and/or tobacco abuse.

[0111] Compounds of the present invention may be administered incombination with other pharmaceutical agents. Preferred pharmaceuticalagents include nicotine receptor partial agonists, opioid antagonists(e.g., naltrexone (including naltrexone depot), antabuse, andnalmefene), dopaminergic agents (e.g., apomorphine), ADD/ADHD agents(e.g., methylphenidate hydrochloride (e.g., Ritalin™ and Concerta™),atomoxetine (e.g., Strattera™), and amphetamines (e.g., Adderall™)) andanti-obesity agents, such as apo-B/MTP inhibitors, 11β-hydroxy steroiddehydrogenase-1 (11β-HSD type 1) inhibitors, peptide YY₃₋₃₆ or analogsthereof, MCR-4 agonists, CCK-A agonists, monoamine reuptake inhibitors,sympathomimetic agents, β₃ adrenergic receptor agonists, dopaminereceptor agonists, melanocyte-stimulating hormone receptor analogs,5-HT2c receptor agonists, melanin concentrating hormone receptorantagonists, leptin, leptin analogs, leptin receptor agonists, galaninreceptor antagonists, lipase inhibitors, bombesin receptor agonists,neuropeptide-Y receptor antagonists (e.g., NPY-5 receptor antagonistssuch as those described herein below), thyromimetic agents,dehydroepiandrosterone or analogs thereof, glucocorticoid receptorantagonists, orexin receptor antagonists, glucagon-like peptide-1receptor agonists, ciliary neurotrophic factors, human agouti-relatedprotein antagonists, ghrelin receptor antagonists, histamine 3 receptorantagonists or inverse agonists, and neuromedin U receptor agonists, andthe like.

[0112] The combination therapy may be administered as (a) a singlepharmaceutical composition which comprises a compound of the presentinvention, at least one additional pharmaceutical agent described hereinand a pharmaceutically acceptable excipient, diluent, or carrier; or (b)two separate pharmaceutical compositions comprising (i) a firstcomposition comprising a compound of the present invention and apharmaceutically acceptable excipient, diluent, or carrier, and (ii) asecond composition comprising at least one additional pharmaceuticalagent described herein and a pharmaceutically acceptable excipient,diluent, or carrier. The pharmaceutical compositions may be administeredsimultaneously or sequentially and in any order.

[0113] In yet another aspect of the present invention, a pharmaceuticalkit is provided for use by a consumer to treat diseases, conditions ordisorders modulated by cannabinoid receptor antagonists in an animal.The kit comprises a) a suitable dosage form comprising a compound of thepresent invention; and b) instructions describing a method of using thedosage form to treat diseases, conditions or disorders that aremodulated by cannabinoid receptor (in particular, the CB1 receptor)antagonists.

[0114] In yet another embodiment of the present invention is apharmaceutical kit comprising: a) a first dosage form comprising (i) acompound of the present invention and (ii) a pharmaceutically acceptablecarrier, excipient or diluent; b) a second dosage form comprising (i) anadditional pharmaceutical agent described herein, and (ii) apharmaceutically acceptable carrier, excipient or diluent; and c) acontainer.

Definitions

[0115] As used herein, the term “alkyl” refers to a hydrocarbon radicalof the general formula C_(n)H_(2n+1). The alkane radical may be straightor branched. For example, the term “(C₁-C₆)alkyl” refers to amonovalent, straight, or branched aliphatic group containing 1 to 6carbon atoms (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,s-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,neopentyl, 3,3-dimethylpropyl, hexyl, 2-methylpentyl, and the like).Similarly, the alkyl portion (i.e., alkyl moiety) of an alkoxy, acyl(e.g., alkanoyl), alkylamino, dialkylamino, and alkylthio group have thesame definition as above. When indicated as being “optionallysubstituted”, the alkane radical or alkyl moiety may be unsubstituted orsubstituted with one or more substituents (generally, one to threesubstituents except in the case of halogen substituents such asperchloro or perfluoroalkyls) independently selected from the group ofsubstituents listed below in the definition for “substituted.”“Halo-substituted alkyl” refers to an alkyl group substituted with oneor more halogen atoms (e.g., fluoromethyl, difluoromethyl,trifluoromethyl, perfluoroethyl, and the like). When substituted, thealkane radicals or alkyl moieties are preferably substituted with 1 to 3fluoro substituents, or 1 or 2 substituents independently selected from(C₁-C₃)alkyl, (C₃-C₆)cycloalkyl, (C₂-C₃)alkenyl, aryl, heteroaryl, 3- to6-membered heterocycle, chloro, cyano, hydroxy, (C₁-C₃)alkoxy, aryloxy,amino, (C₁-C₆)alkyl amino, di-(C₁-C₄)alkyl amino, aminocarboxylate(i.e., (C₁-C₃)alkyl-O—C(O)—NH—), hydroxy(C₂-C₃)alkylamino, or keto(oxo), and more preferably, 1 to 3 fluoro groups, or 1 substituentselected from (C₁-C₃)alkyl, (C₃-C₆)cycloalkyl, (C₆)aryl,6-membered-heteroaryl, 3- to 6-membered heterocycle, (C₁-C₃)alkoxy,(C₁-C₄)alkyl amino or di-(C₁-C₂)alkyl amino. When a carbon atom hasattached thereto geminal alkyl groups, then the alkyls may be takentogether to form a carbocyclic ring. For example, a carbon having twogeminal methyl groups would be equivalent to a cyclopropyl group.

[0116] The terms “partially or fully saturated carbocyclic ring” (alsoreferred to as “partially or fully saturated cycloalkyl”) refers tononaromatic rings that are either partially or fully hydrogenated andmay exist as a single ring, bicyclic ring or a spiral ring. Unlessspecified otherwise, the carbocyclic ring is generally a 3- to8-membered ring. For example, partially or fully saturated carbocyclicrings (or cycloalkyl) include groups such as cyclopropyl, cyclopropenyl,cyclobutyl, cyclobutenyl, cyclopentyl, cyclpentenyl, cyclopentadienyl,cyclohexyl, cyclohexenyl, cyclohexadienyl, norbornyl(bicyclo[2.2.1]heptyl), norbornenyl, bicyclo[2.2.2]octyl, and the like.When designated as being “optionally substituted”, the partiallysaturated or fully saturated cycloalkyl group may be unsubstituted orsubstituted with one or more substituents (typically, one to threesubstituents) independently selected from the group of substituentslisted below in the definition for “substituted.” A substitutedcarbocyclic ring also includes groups wherein the carbocyclic ring isfused to a phenyl ring (e.g., indanyl). The carbocyclic group may beattached to the chemical entity or moiety by any one of the carbon atomswithin the carbocyclic ring system. When substituted, the carbocyclicgroup is preferably substituted with 1 or 2 substituents independentlyselected from (C₁-C₃)alkyl, (C₂-C₃)alkenyl, (C₁-C₆)alkylidenyl, aryl,heteroaryl, 3- to 6-membered heterocycle, chloro, fluoro, cyano,hydroxy, (C₁-C₃)alkoxy, aryloxy, amino, (C₁-C₆)alkyl amino,di-(C₁-C₄)alkyl amino, aminocarboxylate (i.e., (C₁-C₃)alkyl-O—C(O)—NH—),hydroxy(C₂-C₃)alkylamino, or keto (oxo), and more preferably 1 or 2 fromsubstituents independently selected from (C₁-C₂)alkyl, 3- to 6-memberedheterocycle, fluoro, (C₁-C₃)alkoxy, (C₁-C₄)alkyl amino ordi-(C₁-C₂)alkyl amino. Similarly, any cycloalkyl portion of a group(e.g., cycloalkylalkyl, cycloalkylamino, etc.) has the same definitionas above.

[0117] The term “partially saturated or fully saturated heterocyclicring” (also referred to as “partially saturated or fully saturatedheterocycle”) refers to nonaromatic rings that are either partially orfully hydrogenated and may exist as a single ring, bicyclic ring or aspiral ring. Unless specified otherwise, the heterocyclic ring isgenerally a 3- to 6-membered ring containing 1 to 3 heteroatoms(preferably 1 or 2 heteroatoms) independently selected from sulfur,oxygen and/or nitrogen. Partially saturated or fully saturatedheterocyclic rings include groups such as epoxy, aziridinyl,tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, pyrrolidinyl,N-methylpyrrolidinyl, imidazolidinyl, imidazolinyl, piperidinyl,piperazinyl, pyrazolidinyl, 2H-pyranyl, 4H-pyranyl, 2H-chromenyl,oxazinyl, morpholino, thiomorpholino, tetrahydrothienyl,tetrahydrothienyl 1,1-dioxide, and the like. When indicated as being“optionally substituted”, the partially saturated or fully saturatedheterocycle group may be unsubstiuted or substituted with one or moresubstituents (typically, one to three substituents) independentlyselected from the group of substituents listed below in the definitionfor “substituted.” A substituted heterocyclic ring includes groupswherein the heterocyclic ring is fused to an aryl or heteroaryl ring(e.g., 2,3-dihydrobenzofuranyl, 2,3-dihydroindolyl,2,3-dihydrobenzothiophenyl, 2,3-dihydrobenzothiazolyl, etc.). Whensubstituted, the heterocycle group is preferably substituted with 1 or 2substituents independently selected from (C₁-C₃)alkyl,(C₃-C₆)cycloalkyl, (C₂-C₄)alkenyl, aryl, heteroaryl, 3- to 6-memberedheterocycle, chloro, fluoro, cyano, hydroxy, (C₁-C₃)alkoxy, aryloxy,amino, (C₁-C₆)alkyl amino, di-(C₁-C₃)alkyl amino, aminocarboxylate(i.e., (C₁-C₃)alkyl-O—C(O)—NH—), or keto (oxo), and more preferably with1 or 2 substituents independently selected from (C₁-C₃)alkyl,(C₃-C₆)cycloalkyl, (C₆)aryl, 6-membered-heteroaryl, 3- to 6-memberedheterocycle, or fluoro. The heterocyclic group may be attached to thechemical entity or moiety by any one of the ring atoms within theheterocyclic ring system. Similarly, any heterocycle portion of a group(e.g., heterocycle-substituted alkyl, heterocycle carbonyl, etc.) hasthe same definition as above.

[0118] The term “aryl” or “aromatic carbocyclic ring” refers to aromaticmoieties having a single (e.g., phenyl) or a fused ring system (e.g.,naphthalene, anthracene, phenanthrene, etc.). A typical aryl group is a6- to 10-membered aromatic carbocyclic ring(s). When indicated as being“optionally substituted”, the aryl groups may be unsubstituted orsubstituted with one or more substituents (preferably no more than threesubstituents) independently selected from the group of substituentslisted below in the definition for “substituted.” Substituted arylgroups include a chain of aromatic moieties (e.g., biphenyl, terphenyl,phenylnaphthalyl, etc.). When substituted, the aromatic moieties arepreferably substituted with 1 or 2 substituents independently selectedfrom (C₁-C₄)alkyl, (C₂-C₃)alkenyl, aryl, heteroaryl, 3- to 6-memberedheterocycle, bromo, chloro, fluoro, iodo, cyano, hydroxy, (C₁-C₄)alkoxy,aryloxy, amino, (C₁-C₆)alkyl amino, di-(C₁-C₃)alkyl amino, oraminocarboxylate (i.e., (C₁-C₃)alkyl-O—C(O)—NH—), and more preferably, 1or 2 substituents independently selected from (C₁-C₄)alkyl, chloro,fluoro, cyano, hydroxy, or (C₁-C₄)alkoxy. The aryl group may be attachedto the chemical entity or moiety by any one of the carbon atoms withinthe aromatic ring system. Similarly, the aryl portion (i.e., aromaticmoiety) of an aroyl or aroyloxy (i.e., (aryl)-C(O)—O—) has the samedefinition as above.

[0119] The term “heteroaryl” or “heteroaromatic ring” refers to aromaticmoieties containing at least one heteratom (e.g., oxygen, sulfur,nitrogen or combinations thereof) within a 5- to 10-membered aromaticring system (e.g., pyrrolyl, pyridyl, pyrazolyl, indolyl, indazolyl,thienyl, furanyl, benzofuranyl, oxazolyl, imidazolyl, tetrazolyl,triazinyl, pyrimidyl, pyrazinyl, thiazolyl, purinyl, benzimidazolyl,quinolinyl, isoquinolinyl, benzothiophenyl, benzoxazolyl, etc.). Theheteroaromatic moiety may consist of a single or fused ring system. Atypical single heteroaryl ring is a 5- to 6-membered ring containing oneto three heteroatoms independently selected from oxygen, sulfur andnitrogen and a typical fused heteroaryl ring system is a 9- to10-membered ring system containing one to four heteroatoms independentlyselected from oxygen, sulfur and nitrogen. When indicated as being“optionally substituted”, the heteroaryl groups may be unsubstituted orsubstituted with one or more substituents (preferably no more than threesubstituents) independently selected from the group of substituentslisted below in the definition for “substituted.” When substituted, theheteroaromatic moieties are preferably substituted with 1 or 2substituents independently selected from (C₁-C₄)alkyl, (C₂-C₃)alkenyl,aryl, heteroaryl, 3- to 6-membered heterocycle, bromo, chloro, fluoro,iodo, cyano, hydroxy, (C₁-C₄)alkoxy, aryloxy, amino, (C₁-C₆)alkyl amino,di-(C₁-C₃)alkyl amino, or aminocarboxylate (i.e.,(C₁-C₃)alkyl-O—C(O)—NH—), and more preferably, 1 or 2 substituentsindependently selected from (C₁-C₄)alkyl, chloro, fluoro, cyano,hydroxy, (C₁-C₄)alkoxy, (C₁-C₄)alkyl amino or di-(C₁-C₂)alkyl amino. Theheteroaryl group may be attached to the chemical entity or moiety by anyone of the atoms within the aromatic ring system (e.g., imidazol-1-yl,imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, pyrid-2-yl, pyrid-3-yl,pyrid-4-yl, pyrid-5-yl, or pyrid-6-yl). Similarly, the heteroarylportion (i.e., heteroaromatic moiety) of a heteroaroyl or heteroaroyloxy(i.e., (heteroaryl)-C(O)—O—) has the same definition as above.

[0120] The term “acyl” refers to hydrogen, alkyl, partially saturated orfully saturated cycloalkyl, partially saturated or fully saturatedheterocycle, aryl, and heteroaryl substituted carbonyl groups. Forexample, acyl includes groups such as (C₁-C₆)alkanoyl (e.g., formyl,acetyl., propionyl, butyryl, valeryl, caproyl, t-butylacetyl, etc.),(C₃-C₆)cycloalkylcarbonyl (e.g., cyclopropylcarbonyl,cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.),heterocyclic carbonyl (e.g., pyrrolidinylcarbonyl,pyrrolid-2-one-5-carbonyl, piperidinylcarbonyl, piperazinylcarbonyl,tetrahydrofuranylcarbonyl, etc.), aroyl (e.g., benzoyl) and heteroaroyl(e.g., thiophenyl-2-carbonyl, thiophenyl-3-carbonyl, furanyl-2-carbonyl,furanyl-3-carbonyl, 1H-pyrroyl-2-carbonyl, 1H-pyrroyl-3-carbonyl,benzo[b]thiophenyl-2-carbonyl, etc.). In addition, the alkyl,cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl groupmay be any one of the groups described in the respective definitionsabove. When indicated as being “optionally substituted”, the acyl groupmay be unsubstituted or optionally substituted with one or moresubstituents (typically, one to three substituents) independentlyselected from the group of substituents listed below in the definitionfor “substituted” or the alkyl, cycloalkyl, heterocycle, aryl andheteroaryl portion of the acyl group may be substituted as describedabove in the preferred and more preferred list of substituents,respectively.

[0121] The term “substituted” specifically envisions and allows for oneor more substitutions that are common in the art. However, it isgenerally understood by those skilled in the art that the substituentsshould be selected so as to not adversely affect the pharmacologicalcharacteristics of the compound or adversely interfere with the use ofthe medicament. Suitable substituents for any of the groups definedabove include (C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, (C₂-C₆)alkenyl,(C₁-C₆)alkylidenyl, aryl, heteroaryl, 3- to 6-membered heterocycle, halo(e.g., chloro, bromo, iodo and fluoro), cyano, hydroxy, (C₁-C₆)alkoxy,aryloxy, sulfhydryl (mercapto), (C₁-C₆)alkylthio, arylthio, amino, mono-or di-(C₁-C₆)alkyl amino, quaternary ammonium salts, amino(C₁-C₆)alkoxy,aminocarboxylate (i.e., (C₁-C₆)alkyl-O—C(O)—NH—),hydroxy(C₂-C₆)alkylamino, amino(C₁-C₆)alkylthio, cyanoamino, nitro,(C₁-C₆)carbamyl, keto (oxo), acyl, (C₁-C₆)alkyl-CO₂—, glycolyl, glycyl,hydrazino, guanyl, sulfamyl, sulfonyl, sulfinyl, thio(C₁-C₆)alkyl-C(O)—,thio(C₁-C₆)alkyl-CO₂—, and combinations thereof. In the case ofsubstituted combinations, such as “substituted aryl(C₁-C₆)alkyl”, eitherthe aryl or the alkyl group may be substituted, or both the aryl and thealkyl groups may be substituted with one or more substituents(typically, one to three substituents except in the case of perhalosubstitutions). An aryl or heteroaryl substituted carbocyclic orheterocyclic group may be a fused ring (e.g., indanyl,dihydrobenzofuranyl, dihydroindolyl, etc.).

[0122] The term “solvate” refers to a molecular complex of a compoundrepresented by Formula (I) or (II) (including prodrugs andpharmaceutically acceptable salts thereof) with one or more solventmolecules. Such solvent molecules are those commonly used in thepharmaceutical art, which are known to be innocuous to the recipient,e.g., water, ethanol, and the like. The term “hydrate” refers to thecomplex where the solvent molecule is water.

[0123] The term “protecting group” or “Pg” refers to a substituent thatis commonly employed to block or protect a particular functionalitywhile reacting other functional groups on the compound. For example, an“amino-protecting group” is a substituent attached to an amino groupthat blocks or protects the amino functionality in the compound.Suitable amino-protecting groups include acetyl, trifluoroacetyl,t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a “hydroxy-protectinggroup” refers to a substituent of a hydroxy group that blocks orprotects the hydroxy functionality. Suitable protecting groups includeacetyl and silyl. A “carboxy-protecting group” refers to a substituentof the carboxy group that blocks or protects the carboxy functionality.Common carboxy-protecting groups include —CH₂CH₂SO₂Ph, cyanoethyl,2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl,2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl,2-(diphenylphosphino)-ethyl, nitroethyl and the like. For a generaldescription of protecting groups and their use, see T. W. Greene,Protective Groups in Organic Synthesis, John Wiley & Sons, New York,1991.

[0124] The phrase “therapeutically effective amount” means an amount ofa compound of the present invention that (i) treats or prevents theparticular disease, condition, or disorder, (ii) attenuates,ameliorates, or eliminates one or more symptoms of the particulardisease, condition, or disorder, or (iii) prevents or delays the onsetof one or more symptoms of the particular disease, condition, ordisorder described herein.

[0125] The term “animal” refers to humans (male or female), companionanimals (e.g., dogs, cats and horses), food-source animals, zoo animals,marine animals, birds and other similar animal species. “Edible animals”refers to food-source animals such as cows, pigs, sheep and poultry.

[0126] The phrase “pharmaceutically acceptable” indicates that thesubstance or composition must be compatible chemically and/ortoxicologically, with the other ingredients comprising a formulation,and/or the mammal being treated therewith.

[0127] The terms “treating”, “treat”, or “treatment” embrace bothpreventative, i.e., prophylactic, and palliative treatment.

[0128] The terms “modulated by a cannabinoid receptor” or “modulation ofa cannabinoid receptor” refers to the activation or deactivation of acannabinoid receptor. For example, a ligand may act as an agonist,partial agonist, inverse agonist, antagonist, or partial antagonist.

[0129] As used herein, the term “antagonist” includes both fullantagonists and partial antagonists, as well as inverse agonists.

[0130] The term “compounds of the present invention” (unlessspecifically identified otherwise) refer to compounds of Formula (I) andFormula (II), prodrugs thereof, pharmaceutically acceptable salts of thecompounds, and/or prodrugs, and hydrates or solvates of the compounds,salts, and/or prodrugs, as well as, all stereoisomers (includingdiastereoisomers and enantiomers), tautomers and isotopically labeledcompounds.

DETAILED DESCRIPTION

[0131] Compounds of the present invention may be synthesized bysynthetic routes that include processes analogous to those well-known inthe chemical arts, particularly in light of the description containedherein. The starting materials are generally available from commercialsources such as Aldrich Chemicals (Milwaukee, Wis.) or are readilyprepared using methods well known to those skilled in the art (e.g.,prepared by methods generally described in Louis F. Fieser and MaryFieser, Reagents for Organic Synthesis, v.1-19, Wiley, New York(1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl.ed. Springer-Verlag, Berlin, including supplements (also available viathe Beilstein online database)).

[0132] For illustrative purposes, the reaction schemes depicted belowprovide potential routes for synthesizing the compounds of the presentinvention as well as key intermediates. For a more detailed descriptionof the individual reaction steps, see the Examples section below. Thoseskilled in the art will appreciate that other synthetic routes may beused to synthesize the inventive compounds. Although specific startingmaterials and reagents are depicted in the schemes and discussed below,other starting materials and reagents can be easily substituted toprovide a variety of derivatives and/or reaction conditions. Inaddition, many of the compounds prepared by the methods described belowcan be further modified in light of this disclosure using conventionalchemistry well known to those skilled in the art.

[0133] In the preparation of compounds of the present invention,protection of remote functionality (e.g., primary or secondary amine) ofintermediates may be necessary. The need for such protection will varydepending on the nature of the remote functionality and the conditionsof the preparation methods. Suitable amino-protecting groups (NH-Pg)include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC),benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Theneed for such protection is readily determined by one skilled in theart. For a general description of protecting groups and their use, seeT. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons,New York, 1991.

[0134] Scheme I outlines the general procedures one could use to providecompounds of the present invention where A is C(R²) and R² and R³ arehydrogen, alkyl or halo substituted alkyl.

[0135] The pyrazole carboxylic acid (1a) may be prepared using themethods described in U.S. Pat. No. 5,624,941, incorporated herein byreference. Intermediate (1b) may be prepared by condensing the pyrazolecarboxylic acid (a) with a protected α-aminoacetal or protectedα-aminoketal (e.g., N-benzylaminoacetaldehyde dimethyl acetal orN-benzyl-N-(2,2-diethoxyethyl)amine) using conditions well known tothose skilled in the art. For example intermediate (1b) may be formed bycoupling (1a) and the amine in an aprotic solvent (e.g., methylenechloride) at about room temperature using1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and a base(e.g., diisopropylethylamine). Cyclization to the pyridinone (1c) may beaccomplished using procedures described by Dumas, D. J., in J. Org.Chem., 53, 4650-1853 (1988) or by Brimble, M. A., et al., Aust. J.Chem., 41, 1583-1590 (1988). For example, pyridinone (1c) may be formedby treating (1b) with toluenesulfonic acid in refluxing toluene.Introduction of a leaving group (L) and aromatization of the pyridinone(c) to form the aromatic intermediate (1d) may be accomplished usingconventional procedures well-known to those skilled in the art. Forexample, debenzylation/halogenation may be accomplished using phosphorusoxychloride under refluxing conditions. Alternatively, the protectinggroup could be cleaved as a first step, followed by halogenation (e.g.,POCl₃ or SOCl₂ in the presence or absence of a base like triethylamineor pyridine at reflux) or mesylation (e.g., methansulfonic anhydride andtertiary amine base).

[0136] When R⁴ is an amine functionality (e.g., R⁴=an amino group ofFormula (IA) or an amino group substituted with one or more substituentsdescribed above), the amine may be introduced via a coupling reactionbetween intermediate (1d) and the corresponding amino compound (R⁴—H) togive a compound of the present invention where R⁴ is an amino group. Forexample, intermediate (1d) is generally stirred with the desired amine(R⁴—H). The amine may act as the solvent (e.g., butylamine, morpholine,pyrrolidine) or a solvent (e.g., methylene chloride,N,N-dimethylformamide, ethanol) may be added to assist in solubilizationof the reactants and/or provide a media having the appropriate refluxingtemperature to complete the substitution. The reaction may be heated toaccelerate the process. Suitable reaction temperatures range from about−40° C. to 100° C., and are preferably conducted at around 60° C. Inaddition, a suitable base (e.g., triethylamine, diisopropylethylamine)may be employed to quench the acid produced in the process. Suitableamino compounds can be either purchased commercially or easily preparedusing standard procedures well-known to those skilled in the art.Preferred amino compounds (R⁴—H) include4-alkylaminopiperidine-4-carboxamides (Scheme III) and3-alkylaminoazetidine-3-carboxamides that are described below. For adetailed description of representative compounds prepared using theprocedures generally described in Scheme I above where in R⁴ is an aminefunctionality, see Example 1A-1 in the Examples section below.

[0137] Scheme II below outlines the general procedures that may be usedto produce compounds of the present invention where A is N.

[0138] Lithium salt (2b) can be prepared by treatment of methyl ketone(2a) with lithium hexamethyldisilazide at a temperature of about −78° C.in an aprotic solvent such as THF, followed by condensation with diethyloxalate, as described in WO 00/46209. The isolated lithium salt (2b) isthen dissolved in an acid such as acetic acid and nitrosated by dropwiseaddition of aqueous sodium nitrite at a temperature of about 0-10° C.(Tetrahedron, 3, 209 (1958); Bull. Chem. Soc. Jpn. 52, 208 (1979)). Asubstituted hydrazine may then be added directly to the reaction mixtureto afford intermediate (2c). Cyclization of (2c) is accomplished byheating intermediate (2c) and a catalytic amount of an acid such asconcentrated sulfuric acid in a solvent such isopropanol at atemperature of about 60° C. to provide nitrosopyrazole (2d). The nitrosogroup of intermediate (2d) can be reduced by treatment of (2d) withsodium dithionite in a mixture of solvents such as ethyl acetate andwater, affording aminopyrazole (2e), which is reacted with anappropriate amidine (such as formamidine when R³═H) in an aproticsolvent such as 2-ethoxyethanol at an elevated temperature, such asreflux (202° C. for 2-ethoxyethanol) to provide pyrazolopyrimidine (2f).A leaving group (L) is then introduced in preparation for theintroduction of the R⁴ group. For example, chloropyrazolopyrimidineintermediate (2g, where L is Cl) may be prepared by treatment of asuspension of (2f) in an aprotic solvent such as 1,2-dichloroethane withphosphorous oxychloride and heating the resultant suspension to reflux(83° C. for 1,2-dichloroethane). Compounds of formula I or II (A=N) arethen obtained by displacement of the leaving group (e.g., Cl) of (2g)with a nucleophile such as an amine in a solvent such as ethanol at atemperature of about 20-60° C. (see above). For a detailed descriptionof representative compounds prepared using the procedures generallydescribed in Scheme II above wherein R⁴ is an amine functionality, seeExamples 2A-1 and 3A-1 in the Examples section below.

[0139] Numerous amine compounds of Formula (IA) are available fromcommercial sources or prepared by known methods readily available tothose skilled in the art. Representative preparations of amine compoundsof Formula (IA) are illustrated in the Examples below. The4-aminopiperidine-4-carboxamide groups of Formula (IA) and4-amino-4-cyano piperidine groups of Formula (IA) and their benzylprotected precursors may be prepared using the procedures described byP. A. J. Janssen in U.S. Pat. No. 3,161,644, C. van de Westeringh et al.in J. Med. Chem., 7, 619-623 (1964), and K. A. Metwally et al. in J.Med. Chem., 41, 5084-5093 (1998) where the above 4-amino groups areunsubstituted, monosubstituted, disubstituted, or part of a heterocyclicring. Related bicyclic derivatives are described by K. Frohlich et al.in Tetrahedron, 54, 13115-13128 (1998) and references contained therein.Spiro-substituted piperidines of formula (IA) are described by P. A. J.Janssen in U.S. Pat. No. 3,155,670, K. A. Metwally et al. in J. MedChem., 41, 5084-5093 (1998), T. Toda et al. in Bull. Chem. Soc. Japan,44, 3445-3450 (1971), and W. Brandau and S. Samnick in WO 9522544. Thepreparation of 3-aminoazetidine-3-carboxamide is described by A. P.Kozikowski and A. H. Fauq in Synlett, 783-784 (1991). The preparation ofpreferred 4-alkylaminopiperidine-4-carboxamide groups of Formula (IA)are depicted in Scheme III below. The corresponding3-alkylaminoazetidine-3-carboxamides and3-alkylaminopyrolidine-3-carboxamides may be prepared in an analogousfashion. Spiro-substituted derivatives are available by proceduresanalogous to those contained in the above references. A detaileddescription of some representative spiro-substituted amines may be foundin the “Preparation of Key Intermediates” section of the Examples below(see, e.g., I-2A-69d and I-3A-50d).

[0140] The amino group of 4-piperidinone is first protected to provideintermediate (3a). A useful protection group is benzyl. 4-Piperidinoneand derivatives thereof may be purchased commercially from a variety ofsources (e.g., Interchem Corporation, Paramus, N.J. and Sigma-AldrichCo., St. Louis, Mo.). Piperidinone (3a) may then be reacted with thedesired alkylamine and potassium cyanide in an aqueous HCl/ethanolsolvent mixture at about 0° C. to about 30° C. The cyano group isconverted to the corresponding amide with acid and water, or withalkaline hydrogen peroxide in the presence of DMSO (see Y. Sawaki and Y.Ogata in Bull. Chem. Soc. Jpn. 54, 793-799 (1981)). The protecting groupis then removed using conventional methods for the particular protectinggroup employed. For example, a benzyl protecting group may be removed byhydrogenation in the presence of Pd/C. A detailed description of somerepresentative amines having Formula (3c) above may be found in the“Preparation of Key Intermediates” section of the Examples below (see,e.g., I-1A-1f, I-2A-90a, and I-1A-6c).

[0141] Compounds of the present invention where R⁴ is an alkoxy group(i.e., R⁴=a group of Formula (1B) or (1C), may be prepared by treatingintermediate (1d) or (2g) with the desired alcohol in the presence of abase (e.g., potassium t-butoxide, NaH, 1,4-diazabicyclo[2.2.2]octane,diisopropylethylamine, NaHCO₃). The alcohol may act as solvent, or anaprotic solvent may be added to assist in solubilization of thereactants and/or provide a media having the appropriate refluxingtemperature to complete the substitution (e.g., THF, methylene chloride,DMF). Suitable alcohols can be either purchased commercially or easilyprepared using standard procedures well known to those skilled in theart. For a detailed description of representative compounds preparedusing this procedure, see Examples 7A-1, 8A-1, 9A-1 and 12A-1 in theExamples section below.

[0142] An alternative route to compounds where R⁴ is an alkoxy groupinvolves O-alkylation of the pyrazolopyrimidinol (2f) orpyrazolopyrimidinol. The latter intermediate can be prepared bydeprotecting (1c) using standard procedures. Alternatively, thepyrazolopyrimidinol can be prepared by hydrolyzing intermediate (1d),such as by heating with aqueous acid (e.g., HCl) in an appropriatesolvent (e.g., THF). For a detailed description of representativecompounds prepared using this procedure, see Example 10A-1 in theExamples section below.

[0143] For compounds of Formula (I) and (II) where R⁴ is an aminoalkyl,alkylaminoalkyl, or dialkylaminoalkyl group, the leaving group (e.g.,L=Cl) in intermediate (1d) or (2g) may first be displaced with a cyanogroup (e.g., treating with tetrabutylammonium cyanide in the presence of1,4-diazabicyclo[2.2.2]octane (DABCO) in an aprotic solvent (e.g.,acetonitrile) at room temperature). See, e.g., Hocek, et al. Collect.Czech. Chem. Commun. 60, 1386 (1995). The cyano group may then bereduced to the alkyl amine using standard reduction methods well-knownto those skilled in the art (e.g., treating with DIBAL or hydrogen inthe presence of Pd/C). The amino group can then be alkylated usingstandard reductive alkylation procedures. Generally, a Schiff base isformed by reacting the amine with the desired ketone or aldehyde in apolar solvent at a temperature from about 10° C. to about 140° C. forabout 2 to about 24 hours in the presence of 3 Å molecular sieves.Typically, an equivalent or a slight excess of the amino compound isadded to the ketone or aldehyde. Suitable polar solvents includemethylene chloride, 1,2-dichloroethane, dimethyl sulfoxide,dimethylformamide, alcohols (e.g., methanol or ethanol), or mixturesthereof. A preferred solvent is methanol. In the same reaction vessel,the imine may then be reduced to the secondary amine in the presence ofa reducing agent at a temperature from about 0° C. to about 10° C. andthen warmed to a temperature from about 20° C. to about 40° C. for about30 minutes to about 2 hours. Suitable reducing agents includepyridine-borane complex and metal borohydrides, such as sodiumborohydride, sodium triacetoxy borohydride and sodium cyanoborohydride.Suitable aldehydes or ketones include paraformaldehyde, acetaldehyde,acetone, benzaldehyde, and the like.

[0144] Alternatively, the amino alkyl group may be introduced using themethods described by Hocek, et al. in Tetrahedron, 53(6), 2291-2302(1997). Intermediate (1d), where L=Cl, Br or OTf, or intermediate (29)may be converted to the acetyl-derivative compound by reactingintermediate (1 d) or (2q) with 1-ethoxyvinyl)tri-n-butyltin underPd(PPh₃)₄ catalysis followed by hydrolysis using a mixture of acetoneand aqueous HCl (or DMF/aq. HCl mixture) at reflux temperatures. Theacetyl group may then be converted to an amine or substituted amine byreductive amination, a process well-known to those skilled in the art.An exemplary procedure employs the desired amine salt (e.g., ammoniumchloride, methylammonium chloride, allylammonium chloride,cyclopropylammonium chloride, cyclohexylammonium chloride,dimethylammonium chloride, benzylammonium chloride, etc.) and a reducingagent (e.g., NaBH₄, NaBH₃CN, or triacetoxyborohydride) in polar solventat room temperature. See Abdel-Magid, et al., J. Org. Chem., 61,3849-3862 (1996) for a wide variety of aldehydes, ketones and aminesthat may be used in either the reductive alkylation or the reductiveamination.

[0145] Compounds of Formula (I) above where R⁴ contains a primary orsecondary amine can be alkylated, sulfonated and/or acylated to provideadditional derivatives (e.g., alkylamines, dialkylamines, sulfonamides,amides, carbamates, ureas, etc.) using standard procedures well known tothose skilled in the art. In some cases the amine is protected, and mustbe unmasked before further functionalization. For a more detaileddescription of representative compounds prepared using these procedures,see Examples 4A-1, 5A-1 and 6A-1 in the Examples section below.

[0146] Alternatively, compounds of Formula (I) or (II) where R⁴ is ahydroxy or alkoxy substituted alkyl group may be produced by replacingthe chlorine group of intermediate (1d), L=Cl, or (2g) with the desiredelectrophile using procedures described by Sugimoto, et al., inTetrahedron Letters, 40, 2139-2140 (1999). The intermediate (1d), L=Cl,or (2a) may be reacted with lithium n-butanetellurolate (telluriumreacted with n-butyllithium) in an aprotic solvent (e.g., THF) at −78°C. followed by the addition of the desired electrophile (e.g.,acetaldehyde, benzaldehyde, acetone, methylethyl ketone, etc.) and thenwarmed to room temperature to form the desired hydroxyalkyl derivative.Alternately, the hydroxy derivative may be formed using the proceduresdescribed by Leonard, et al., in J. Org. Chem., 44(25), 4612-4616(1979). Intermediate (1d), L=Cl, or (29) is treated with n-butyl lithiumto form the carbanion at −78° C., followed by reaction with the desiredelectrophile (e.g., ketone or aldehyde) to form the hydroxyalkylderivative.

[0147] In yet another approach, an aroyl derivative of formula (I) or(II), where R⁴=aroyl, can be prepared by the procedures described byMiyashita, et al., in Chem. Pharm. Bull, 46(30), 390-399 (1998). Thearoyl group can then be reduced to the corresponding secondary alcoholby treating with a reducing agent such as lithium aluminum hydride. Thetertiary alcohol can be obtained upon treatment with an alkyl metalreagent, such as an alkyl Grignard reagent, in a suitable solvent (e.g.,tetrahydrofuran, diethyl ether). Finally, an amine could be introducedby reductive amination (see above).

[0148] In the above examples, the resultant hydroxyalkyl group can thenbe alkylated or acylated to form the desired alkoxy or acylate (e.g.,(alkyl)-C(O)—O—, (aryl)-C(O)—O—, (heteroaryl)-C(O)—O—, etc.) usingstandard procedures well-known to those skilled in the art.Alternatively, the hydroxy group may be condensed with other moieties toprovide a variety of substituents (e.g., sulfamyl, sulfonyl, etc.). Theaminoalkyl group could be modified in a similar fashion to give amides,sulfonamides, etc.

[0149] An alternate route for the synthesis of intermediate (2e) isshown in Scheme IV below.

[0150] The starting pyrazolo ester (R=alkyl group) may be prepared byprocedures described in U.S. Pat. No. 5,624,941 and is incorporatedherein by reference. The bromo intermediate (4b) may be prepared from(4a) using conventional bromination procedures well-known to thoseskilled in the art. For example, the pyrazolo ester may be treated withbromine in a protic solvent (e.g., acetic acid) at a temperature fromabout 10° C. to about −10° C. Amine deriviative (4c), which isequivalent to (2e) when R=Et, may then be prepared bypalladium-catalyzed methods described by X. Huang and S. L. Buchwald inOrg. Lett., 3, 3417-3419 (2001), and with references contained therein.

[0151] Conventional methods and/or techniques of separation andpurification known to one of ordinary skill in the art can be used toisolate the compounds of the present invention, as well as the variousintermediates related thereto. Such techniques will be well known to oneof ordinary skill in the art and may include, for example, all types ofchromatography (high pressure liquid chromatography (HPLC), columnchromatography using common adsorbents such as silica gel, andthin-layer chromatography), recrystallization, and differential (i.e.,liquid-liquid) extraction techniques.

[0152] The compounds of the present invention may be isolated and usedper se or in the form of its pharmaceutically acceptable salt, solvateand/or hydrate. The term “salts” refers to inorganic and organic saltsof a compound of the present invention. These salts can be prepared insitu during the final isolation and purification of a compound, or byseparately reacting the compound, N-oxide, or prodrug with a suitableorganic or inorganic acid or base and isolating the salt thus formed.Representative salts include the hydrobromide, hydrochloride,hydroiodide, sulfate, bisulfate, nitrate, acetate, trifluoroacetate,oxalate, besylate, palmitiate, pamoate, malonate, stearate, laurate,malate, borate, benzoate, lactate, phosphate, hexafluorophosphate,benzene sulfonate, tosylate, formate, citrate, maleate, fumarate,succinate, tartrate, naphthylate, mesylate, glucoheptonate,lactobionate, and laurylsulphonate salts, and the like. These mayinclude cations based on the alkali and alkaline earth metals, such assodium, lithium, potassium, calcium, magnesium, and the like, as well asnon-toxic ammonium, quaternary ammonium, and amine cations including,but not limited to, ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine,and the like. See, e.g., Berge, et al., J. Pharm. Sci., 66, 1-19 (1977).

[0153] The term “prodrug” means a compound that is transformed in vivoto yield a compound of Formula (I) or a pharmaceutically acceptablesalt, hydrate or solvate of the compound. The transformation may occurby various mechanisms, such as through hydrolysis in blood. A discussionof the use of prodrugs is provided by T. Higuchi and W. Stella,“Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A. C. S. SymposiumSeries, and in Bioreversible Carriers in Drug Design, ed. Edward B.Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0154] For example, if a compound of the present invention contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl, 1-(alkanoyloxy)ethylhaving from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl havingfrom 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbonatoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbonatoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N-(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

[0155] Similarly, if a compound of the present invention contains analcohol functional group, a prodrug can be formed by the replacement ofthe hydrogen atom of the alcohol group with a group such as(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanoyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from the removalof a hydroxyl group of the hemiacetal form of a carbohydrate).

[0156] If a compound of the present invention incorporates an aminefunctional group, a prodrug can be formed by the replacement of ahydrogen atom in the amine group with a group such as R-carbonyl,RO-carbonyl, NRR′-carbonyl where R and R′ are each independently(C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, benzyl, or R-carbonyl is a naturalα-aminoacyl or natural x-aminoacyl-natural α-aminoacyl, —C(OH)C(O)OY′wherein Y′ is H, (C₁-C₆)alkyl or benzyl, —C(OY₀)Yl wherein Y₀ is(C₁-C₄)alkyl and Y₁ is (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl,amino(C₁-C₄)alkyl or mono-N— or di-N,N-(C₁-C₆)alkylaminoalkyl, —C(Y₂)Y₃wherein Y₂ is H or methyl and Y₃ is mono-N— or di-N,N-(C₁-C₆)alkylamino,morpholino, piperidin-1-yl or pyrrolidin-1-yl.

[0157] The compounds of the present invention may contain asymmetric orchiral centers, and, therefore, exist in different stereoisomeric forms.It is intended that all stereoisomeric forms of the compounds of thepresent invention as well as mixtures thereof, including racemicmixtures, form part of the present invention. In addition, the presentinvention embraces all geometric and positional isomers. For example, ifa compound of the present invention incorporates a double bond or afused ring, both the cis- and trans- forms, as well as mixtures, areembraced within the scope of the invention. Both the single positionalisomers and mixture of positional isomers resulting from the N-oxidationof the pyrimidine and pyrazine rings are also within the scope of thepresent invention.

[0158] Diastereomeric mixtures can be separated into their individualdiastereoisomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereoisomers and converting (e.g., hydrolyzing) theindividual diastereoisomers to the corresponding pure enantiomers. Also,some of the compounds of the present invention may be atropisomers(e.g., substituted biaryls) and are considered as part of thisinvention. Enantiomers can also be separated by use of a chiral HPLCcolumn.

[0159] The compounds of the present invention may exist in unsolvated aswell as solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms.

[0160] It is also possible that the compounds of the present inventionmay exist in different tautomeric forms, and all such forms are embracedwithin the scope of the invention. The term “tautomer” or “tautomericform” refers to structural isomers of different energies which areinterconvertible via a low energy barrier. For example, proton tautomers(also known as prototropic tautomers) include interconversions viamigration of a proton, such as keto-enol and imine-enamineisomerizations. Valence tautomers include interconversions byreorganization of some of the bonding electrons.

[0161] The present invention also embraces isotopically-labeledcompounds of the present invention which are identical to those recitedherein, but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number usually found in nature. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine,iodine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O,¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ¹²³I, ¹²⁵I and ³⁶Cl, respectively.

[0162] Certain isotopically-labeled compounds of the present invention(e.g., those labeled with ³H and ¹⁴C) are useful in compound and/orsubstrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14(i.e., ¹⁴C) isotopes are particularly preferred for their ease ofpreparation and detectability. Further, substitution with heavierisotopes such as deuterium (i.e., ²H) may afford certain therapeuticadvantages resulting from greater metabolic stability (e.g., increasedin vivo half-life or reduced dosage requirements) and hence may bepreferred in some circumstances. Positron emitting isotopes such as ¹⁵O,¹³N, ¹¹C, and ¹⁸F are useful for positron emission tomography (PET)studies to examine substrate receptor occupancy. Isotopically labeledcompounds of the present invention can generally be prepared byfollowing procedures analogous to those disclosed in the Schemes and/orin the Examples herein below, by substituting an isotopically labeledreagent for a non-isotopically labeled reagent.

[0163] Compounds of the present invention are useful for treatingdiseases, conditions and/or disorders modulated by cannabinoid receptorantagonists; therefore, another embodiment of the present invention is apharmaceutical composition comprising a therapeutically effective amountof a compound of the present invention and a pharmaceutically acceptableexcipient, diluent or carrier.

[0164] A typical formulation is prepared by mixing a compound of thepresent invention and a carrier, diluent or excipient. Suitablecarriers, diluents and excipients are well known to those skilled in theart and include materials such as carbohydrates, waxes, water solubleand/or swellable polymers, hydrophilic or hydrophobic materials,gelatin, oils, solvents, water, and the like. The particular carrier,diluent or excipient used will depend upon the means and purpose forwhich the compound of the present invention is being applied. Solventsare generally selected based on solvents recognized by persons skilledin the art as safe (GRAS) to be administered to a mammal. In general,safe solvents are non-toxic aqueous solvents such as water and othernon-toxic solvents that are soluble or miscible in water. Suitableaqueous solvents include water, ethanol, propylene glycol, polyethyleneglycols (e.g., PEG400, PEG300), etc. and mixtures thereof. Theformulations may also include one or more buffers, stabilizing agents,surfactants, wetting agents, lubricating agents, emulsifiers, suspendingagents, preservatives, antioxidants, opaquing agents, glidants,processing aids, colorants, sweeteners, perfuming agents, flavoringagents and other known additives to provide an elegant presentation ofthe drug (i.e., a compound of the present invention or pharmaceuticalcomposition thereof) or aid in the manufacturing of the pharmaceuticalproduct (i.e., medicament).

[0165] The formulations may be prepared using conventional dissolutionand mixing procedures. For example, the bulk drug substance (i.e.,compound of the present invention or stabilized form of the compound(e.g., complex with a cyclodextrin derivative or other knowncomplexation agent)) is dissolved in a suitable solvent in the presenceof one or more of the excipients described above. The compound of thepresent invention is typically formulated into pharmaceutical dosageforms to provide an easily controllable dosage of the drug and to givethe patient an elegant and easily handleable product.

[0166] The pharmaceutical composition (or formulation) for applicationmay be packaged in a variety of ways depending upon the method used foradministering the drug. Generally, an article for distribution includesa container having deposited therein the pharmaceutical formulation inan appropriate form. Suitable containers are well-known to those skilledin the art and include materials such as bottles (plastic and glass),sachets, ampoules, plastic bags, metal cylinders, and the like. Thecontainer may also include a tamper-proof assemblage to preventindiscreet access to the contents of the package. In addition, thecontainer has deposited thereon a label that describes the contents ofthe container. The label may also include appropriate warnings.

[0167] The present invention further provides a method of treatingdiseases, conditions and/or disorders modulated by cannabinoid receptorantagonists in an animal that includes administering to an animal inneed of such treatment a therapeutically effective amount of a compoundof the present invention or a pharmaceutical composition comprising aneffective amount of a compound of the present invention and apharmaceutically acceptable excipient, diluent, or carrier. The methodis particularly useful for treating diseases, conditions and/ordisorders modulated by cannabinoid receptor (in particular, CB1receptor) antagonists.

[0168] Preliminary investigations have indicated that the followingdiseases, conditions, and/or disorders are modulated by cannabinoidreceptor antagonists: eating disorders (e.g., binge eating disorder,anorexia, and bulimia), weight loss or control (e.g., reduction incalorie or food intake, and/or appetite suppression), obesity,depression, atypical depression, bipolar disorders, psychoses,schizophrenia, behavioral addictions, suppression of reward-relatedbehaviors (e.g., conditioned place avoidance, such as suppression ofcocaine- and morphine-induced conditioned place preference), substanceabuse, addictive disorders, impulsivity, alcoholism (e.g., alcoholabuse, addiction and/or dependence including treatment for abstinence,craving reduction and relapse prevention of alcohol intake), tobaccoabuse (e.g., smoking addiction, cessation and/or dependence includingtreatment for craving reduction and relapse prevention of tobaccosmoking), dementia (including memory loss, Alzheimer's disease, dementiaof aging, vascular dementia, mild cognitive impairment, age-relatedcognitive decline, and mild neurocognitive disorder), sexual dysfunctionin males (e.g., erectile difficulty), seizure disorders, epilepsy,inflammation, gastrointestinal disorders (e.g., dysfunction ofgastrointestinal motility or intestinal propulsion), attention deficitdisorder (ADD including attention deficit hyperactivity disorder(ADHD)), Parkinson's disease, and type II diabetes. Accordingly, thecompounds of the present invention described herein are useful intreating diseases, conditions, or disorders that are modulated bycannabinoid receptor antagonists. Consequently, the compounds of thepresent invention (including the compositions and processes usedtherein) may be used in the manufacture of a medicament for thetherapeutic applications described herein.

[0169] Other diseases, conditions and/or disorders for which cannabinoidreceptor antagonists may be effective include: premenstrual syndrome orlate luteal phase syndrome, migraines, panic disorder, anxiety,post-traumatic syndrome, social phobia, cognitive impairment innon-demented individuals, non-amnestic mild cognitive impairment, postoperative cognitive decline, disorders associated with impulsivebehaviours (such as, disruptive behaviour disorders (e.g.,anxiety/depression, executive function improvement, tic disorders,conduct disorder and/or oppositional defiant disorder), adultpersonality disorders (e.g., borderline personality disorder andantisocial personality disorder), diseases associated with impulsivebehaviours (e.g., substance abuse, paraphilias and self-mutilation), andimpulse control disorders (e.g., intermittene explosive disorder,kleptomania, pyromania, pathological gambling, and trichotillomania)),obsessive compulsive disorder, chronic fatigue syndrome, sexualdysfunction in males (e.g., premature ejaculation), sexual dysfunctionin females, disorders of sleep (e.g., sleep apnea), autism, mutism,neurodengenerative movement disorders, spinal cord injury, damage of thecentral nervous system (e.g., trauma), stroke, neurodegenerativediseases or toxic or infective CNS diseases (e.g., encephalitis ormeningitis), cardiovascular disorders (e.g., thrombosis), and diabetes.

[0170] The compounds of the present invention can be administered to apatient at dosage levels in the range of from about 0.7 mg to about7,000 mg per day. For a normal adult human having a body weight of about70 kg, a dosage in the range of from about 0.01 mg to about 100 mg perkilogram body weight is typically sufficient. However, some variabilityin the general dosage range may be required depending upon the age andweight of the subject being treated, the intended route ofadministration, the particular compound being administered and the like.The determination of dosage ranges and optimal dosages for a particularpatient is well within the ability of one of ordinary skill in the arthaving the benefit of the instant disclosure. It is also noted that thecompounds of the present invention can be used in sustained release,controlled release, and delayed release formulations, which forms arealso well known to one of ordinary skill in the art.

[0171] The compounds of this invention may also be used in conjunctionwith other pharmaceutical agents for the treatment of the diseases,conditions and/or disorders described herein. Therefore, methods oftreatment that include administering compounds of the present inventionin combination with other pharmaceutical agents are also provided.Suitable pharmaceutical agents that may be used in combination with thecompounds of the present invention include anti-obesity agents such asapolipoprotein-B secretion/microsomal triglyceride transfer protein(apo-B/MTP) inhibitors, 11β-hydroxy steroid dehydrogenase-1 (11-HSDtype 1) inhibitors, peptide YY₃₋₃₆ or analogs thereof, MCR-4 agonists,cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (suchas sibutramine), sympathomimetic agents, P3 adrenergic receptoragonists, dopamine agonists (such as bromocriptine),melanocyte-stimulating hormone receptor analogs, 5HT2c agonists, melaninconcentrating hormone antagonists, leptin (the OB protein), leptinanalogs, leptin receptor agonists, galanin antagonists, lipaseinhibitors (such as tetrahydrolipstatin, i.e. orlistat), anorecticagents (such as a bombesin agonist), Neuropeptide-Y receptor antagonists(e.g., NPY Y5 receptor antagonists, such as the spiro compoundsdescribed in U.S. Pat. Nos. 6,566,367; 6,649,624; 6,638,942; 6,605,720;6,495,559; 6,462,053; 6,388,077; 6,335,345; and 6,326,375; USPublication Nos. 2002/0151456 and 2003/036652; and PCT Publication Nos.WO 03/010175. WO 03/082190 and WO 02/048152), thyromimetic agents,dehydroepiandrosterone or an analog thereof, glucocorticoid receptoragonists or antagonists, orexin receptor antagonists, glucagon-likepeptide-1 receptor agonists, ciliary neurotrophic factors (such asAxokine™ available from Regeneron Pharmaceuticals, Inc., Tarrytown, N.Y.and Procter & Gamble Company, Cincinnati, Ohio), human agouti-relatedproteins (AGRP), ghrelin receptor antagonists, histamine 3 receptorantagonists or inverse agonists, neuromedin U receptor agonists and thelike. Other anti-obesity agents, including the preferred agents setforth hereinbelow, are well known, or will be readily apparent in lightof the instant disclosure, to one of ordinary skill in the art.

[0172] Especially preferred are anti-obesity agents selected from thegroup consisting of orlistat, sibutramine, bromocriptine, ephedrine,leptin, pseudoephedrine; peptide YY₃₃₆ or an analog thereof; and2-oxo-N-(5-phenylpyrazinyl)spiro-[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide.Preferably, compounds of the present invention and combination therapiesare administered in conjunction with exercise and a sensible diet.

[0173] Representative anti-obesity agents for use in the combinations,pharmaceutical compositions, and methods of the invention can beprepared using methods known to one of ordinary skill in the art, forexample, sibutramine can be prepared as described in U.S. Pat. No.4,929,629; bromocriptine can be prepared as described in U.S. Pat. Nos.3,752,814 and 3,752,888; orlistat can be prepared as described in U.S.Pat. Nos. 5,274,143; 5,420,305; 5,540,917; and 5,643,874; PYY₃₋₃₆(including analogs) can be prepared as described in US Publication No.2002/0141985 and WO 03/027637; and the NPY Y5 receptor antagonist2-oxo-N-(5-phenylpyrazinyl)spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamidecan be prepared as described in US Publication No. 2002/0151456. Otheruseful NPY Y5 receptor antagonists include those described in PCTPublication No. 03/082190, such as3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-1 (3H),4′-piperidine]-1′-carboxamide;3-oxo-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2-yl)-spiro-[isobenzofuran-1(3H), 4′-piperidine]-1′-carboxamide;N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro-[isobenzofuran-1 (3H),[4′-piperidine]-1′-carboxamide; trans-3′-oxo-N-(5-phenyl-2-pyrimidinyl)]spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide;trans-3′-oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide;trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4-azaiso-benzofuran-1(3H),1′-cyclohexane]-4′-carboxamide;trans-N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-[(3H),1′-cyclohexane]-4′-carboxamide;trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide;trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide;trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide;trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide;trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide;trans-3-oxo-N-(2-phenyl-1,2,3-triazol-4-yl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide; and pharmaceutically acceptablesalts and esters thereof. All of the above recited U.S. patents andpublications are incorporated herein by reference.

[0174] Other suitable pharmaceutical agents that may be administered incombination with the compounds of the present invention include agentsdesigned to treat tobacco abuse (e.g., nicotine receptor partialagonists, bupropion hypochloride (also known under the tradename Zyban™)and nicotine replacement therapies), agents to treat erectiledysfunction (e.g., dopaminergic agents, such as apomorphine), ADD/ADHDagents (e.g., Ritalin™, Strattera™, Concerta™ and Adderall™), and agentsto treat alcoholism, such as opioid antagonists (e.g., naltrexone (alsoknown under the tradename ReVia™) and nalmefene), disulfiram (also knownunder the tradename Antabuse™), and acamprosate (also known under thetradename Campral™)). In addition, agents for reducing alcoholwithdrawal symptoms may also be co-administered, such asbenzodiazepines, beta-blockers, clonidine, carbamazepine, pregabalin,and gabapentin (Neurontin™). Treatment for alcoholism is preferablyadministered in combination with behavioral therapy including suchcomponents as motivational enhancement therapy, cognitive behavioraltherapy, and referral to self-help groups, including Alcohol Anonymous(AA).

[0175] Other pharmaceutical agents that may be useful includeantihypertensive agents; anti-inflammatory agents (e.g., COX-2inhibitors); antidepressants (e.g., fluoxetine hydrochloride (Prozac™));cognitive improvement agents (e.g., donepezil hydrochloride (Aircept™)and other acetylcholinesterase inhibitors); neuroprotective agents(e.g., memantine); antipsychotic medications (e.g., ziprasidone(Geodon™), risperidone (Risperdal™), and olanzapine (Zyprexa™)); insulinand insulin analogs (e.g., LysPro insulin); GLP-1 (7-37)(insulinotropin) and GLP-1 (7-36)—NH₂; sulfonylureas and analogsthereof: chlorpropamide, glibenclamide, tolbutamide, tolazamide,acetohexamide, Glypizide®, glimepiride, repaglinide, meglitinide;biguanides: metformin, phenformin, buformin; α2-antagonists andimidazolines: midaglizole, isaglidole, deriglidole, idazoxan, efaroxan,fluparoxan; other insulin secretagogues: linogliride, A-4166;glitazones: ciglitazone, Actos® (pioglitazone), englitazone,troglitazone, darglitazone, Avandia® (BRL49653); fatty acid oxidationinhibitors: clomoxir, etomoxir; α-glucosidase inhibitors: acarbose,miglitol, emiglitate, voglibose, MDL-25,637, camiglibose, MDL-73,945;β-agonists: BRL 35135, BRL 37344, RO 16-8714, ICI D7114, CL 316,243;phosphodiesterase inhibitors: L-386,398; lipid-lowering agents:benfluorex: fenfluramine; vanadate and vanadium complexes (e.g.,Naglivan®) and peroxovanadium complexes; amylin antagonists; glucagonantagonists; gluconeogenesis inhibitors; somatostatin analogs;antilipolytic agents: nicotinic acid, acipimox, WAG 994, pramlintide(Symlin™), AC 2993, nateglinide, aldose reductase inhibitors (e.g.,zopolrestat), glycogen phosphorylase inhibitors, sorbitol dehydrogenaseinhibitors, sodium-hydrogen exchanger type 1 (NHE-1) inhibitors and/orcholesterol biosynthesis inhibitors or cholesterol absorptioninhibitors, especially a HMG-CoA reductase inhibitor (e.g., atorvastatinor the hemicalcium salt thereof), or a HMG-CoA synthase inhibitor, or aHMG-CoA reductase or synthase gene expression inhibitor, a CETPinhibitor, a bile acid sequesterant, a fibrate, an ACAT inhibitor, asqualene synthetase inhibitor, an anti-oxidant or niacin. The compoundsof the present invention may also be administered in combination with anaturally occurring compound that acts to lower plasma cholesterollevels. Such naturally occurring compounds are commonly callednutraceuticals and include, for example, garlic extract, Hoodia plantextracts, and niacin.

[0176] The dosage of the additional pharmaceutical agent is generallydependent upon a number of factors including the health of the subjectbeing treated, the extent of treatment desired, the nature and kind ofconcurrent therapy, if any, and the frequency of treatment and thenature of the effect desired. In general, the dosage range of theadditional pharmaceutical agent is in the range of from about 0.001 mgto about 100 mg per kilogram body weight of the individual per day,preferably from about 0.1 mg to about 10 mg per kilogram body weight ofthe individual per day. However, some variability in the general dosagerange may also be required depending upon the age and weight of thesubject being treated, the intended route of administration, theparticular anti-obesity agent being administered and the like. Thedetermination of dosage ranges and optimal dosages for a particularpatient is also well within the ability of one of ordinary skill in theart having the benefit of the instant disclosure.

[0177] According to the methods of the invention, a compound of thepresent invention or a combination of a compound of the presentinvention and at least one additional pharmaceutical agent isadministered to a subject in need of such treatment, preferably in theform of a pharmaceutical composition. In the combination aspect of theinvention, the compound of the present invention and at least one otherpharmaceutical agent (e.g., anti-obesity agent, nicotine receptorpartial agonist, dopaminergic agent, or opioid antagonist) may beadministered either separately or in the pharmaceutical compositioncomprising both. It is generally preferred that such administration beoral. However, if the subject being treated is unable to swallow, ororal administration is otherwise impaired or undesirable, parenteral ortransdermal administration may be appropriate.

[0178] According to the methods of the invention, when a combination ofa compound of the present invention and at least one otherpharmaceutical agent are administered together, such administration canbe sequential in time or simultaneous with the simultaneous method beinggenerally preferred. For sequential administration, a compound of thepresent invention and the additional pharmaceutical agent can beadministered in any order. It is generally preferred that suchadministration be oral. It is especially preferred that suchadministration be oral and simultaneous. When a compound of the presentinvention and the additional pharmaceutical agent are administeredsequentially, the administration of each can be by the same or bydifferent methods.

[0179] According to the methods of the invention, a compound of thepresent invention or a combination of a compound of the presentinvention and at least one additional pharmaceutical agent (referred toherein as a “combination”) is preferably administered in the form of apharmaceutical composition. Accordingly, a compound of the presentinvention or a combination can be administered to a patient separatelyor together in any conventional oral, rectal, transdermal, parenteral,(for example, intravenous, intramuscular, or subcutaneous)intracisternal, intravaginal, intraperitoneal, intravesical, local (forexample, powder, ointment or drop), or buccal, or nasal, dosage form.

[0180] Compositions suitable for parenteral injection generally includepharmaceutically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions, or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Suitable aqueous and nonaqueous carriers or diluents (including solventsand vehicles) include water, ethanol, polyols (propylene glycol,polyethylene glycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil) and injectable organic esters such asethyl oleate. Proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions, and by the use of surfactants.

[0181] These compositions may also contain excipients such aspreserving, welting, emulsifying, and dispersing agents. Prevention ofmicroorganism contamination of the compositions can be accomplished withvarious antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, and the like. It may also bedesirable to include isotonic agents, for example, sugars, sodiumchloride, and the like. Prolonged absorption of injectablepharmaceutical compositions can be brought about by the use of agentscapable of delaying absorption, for example, aluminum monostearate andgelatin.

[0182] Solid dosage forms for oral administration include capsules,tablets, powders, and granules. In such solid dosage forms, a compoundof the present invention or a combination is admixed with at least oneinert excipient, diluent or carrier. Suitable excipients, diluents orcarriers include materials such as sodium citrate or dicalcium phosphateor (a) fillers or extenders (e.g., starches, lactose, sucrose, mannitol,silicic acid and the like); (b) binders (e.g., carboxymethylcellulose,alginates, gelatin, polyvinylpyrrolidone, sucrose, acacia and the like);(c) humectants (e.g., glycerol and the like); (d) disintegrating agents(e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginicacid, certain complex silicates, sodium carbonate and the like); (e)solution retarders (e.g., paraffin and the like); (f) absorptionaccelerators (e.g., quaternary ammonium compounds and the like); (g)wetting agents (e.g., cetyl alcohol, glycerol monostearate and thelike); (h) adsorbents (e.g., kaolin, bentonite and the like); and/or (i)lubricants (e.g., talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate and the like). In the caseof capsules and tablets, the dosage forms may also comprise bufferingagents. Solid compositions of a similar type may also be used as fillersin soft or hard filled gelatin capsules using such excipients as lactoseor milk sugar, as well as high molecular weight polyethylene glycols,and the like.

[0183] Solid dosage forms such as tablets, dragees, capsules, andgranules can be prepared with coatings and shells, such as entericcoatings and others well known in the art. They may also containopacifying agents, and can also be of such composition that they releasethe compound of the present invention and/or the additionalpharmaceutical agent in a delayed manner. Examples of embeddingcompositions that can be used are polymeric substances and waxes. Thedrug can also be in micro-encapsulated form, if appropriate, with one ormore of the above-mentioned excipients.

[0184] Liquid dosage forms for oral administration includepharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs. In addition to the compound of the present invention or thecombination, the liquid dosage form may contain inert diluents commonlyused in the art, such as water or other solvents, solubilizing agentsand emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseedoil, groundnut oil, corn germ oil, olive oil, castor oil, sesame seedoil and the like), glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan, or mixtures of thesesubstances, and the like.

[0185] Besides such inert diluents, the composition can also includeexcipients, such as wetting agents, emulsifying and suspending agents,sweetening, flavoring, and perfuming agents.

[0186] Suspensions, in addition to the compound of the present inventionor the combination, may further comprise carriers such as suspendingagents, e.g., ethoxylated isostearyl alcohols, polyoxyethylene sorbitoland sorbitan esters, microcrystalline cellulose, aluminum metahydroxide,bentonite, agar-agar, and tragacanth, or mixtures of these substances,and the like.

[0187] Compositions for rectal or vaginal administration preferablycomprise suppositories, which can be prepared by mixing a compound ofthe present invention or a combination with suitable non-irritatingexcipients or carriers, such as cocoa butter, polyethylene glycol or asuppository wax which are solid at ordinary room temperature but liquidat body temperature and therefore melt in the rectum or vaginal cavitythereby releasing the active component(s).

[0188] Dosage forms for topical administration of the compounds of thepresent invention and combinations of the compounds of the presentinvention with anti-obesity agents may comprise ointments, powders,sprays and inhalants. The drugs are admixed under sterile conditionswith a pharmaceutically acceptable excipient, diluent or carrier, andany preservatives, buffers, or propellants that may be required.Ophthalmic formulations, eye ointments, powders, and solutions are alsointended to be included within the scope of the present invention.

[0189] The following paragraphs describe exemplary formulations,dosages, etc. useful for non-human animals. The administration of thecompounds of the present invention and combinations of the compounds ofthe present invention with anti-obesity agents can be effected orally ornon-orally (e.g., by injection).

[0190] An amount of a compound of the present invention or combinationof a compound of the present invention with an anti-obesity agent isadministered such that an effective dose is received. Generally, a dailydose that is administered orally to an animal is between about 0.01 andabout 1,000 mg/kg of body weight, preferably between about 0.01 andabout 300 mg/kg of body weight.

[0191] Conveniently, a compound of the present invention (orcombination) can be carried in the drinking water so that a therapeuticdosage of the compound is ingested with the daily water supply. Thecompound can be directly metered into drinking water, preferably in theform of a liquid, water-soluble concentrate (such as an aqueous solutionof a water-soluble salt).

[0192] Conveniently, a compound of the present invention (orcombination) can also be added directly to the feed, as such, or in theform of an animal feed supplement, also referred to as a premix orconcentrate. A premix or concentrate of the compound in an excipient,diluent or carrier is more commonly employed for the inclusion of theagent in the feed. Suitable carriers are liquid or solid, as desired,such as water, various meals such as alfalfa meal, soybean meal,cottonseed oil meal, linseed oil meal, corncob meal and corn meal,molasses, urea, bone meal, and mineral mixes such as are commonlyemployed in poultry feeds. A particularly effective carrier is therespective animal feed itself; that is, a small portion of such feed.The carrier facilitates uniform distribution of the compound in thefinished feed with which the premix is blended. Preferably, the compoundis thoroughly blended into the premix and, subsequently, the feed. Inthis respect, the compound may be dispersed or dissolved in a suitableoily vehicle such as soybean oil, corn oil, cottonseed oil, and thelike, or in a volatile organic solvent and then blended with thecarrier. It will be appreciated that the proportions of compound in theconcentrate are capable of wide variation since the amount of thecompound in the finished feed may be adjusted by blending theappropriate proportion of premix with the feed to obtain a desired levelof compound.

[0193] High potency concentrates may be blended by the feed manufacturerwith proteinaceous carrier such as soybean oil meal and other meals, asdescribed above, to produce concentrated supplements, which are suitablefor direct feeding to animals. In such instances, the animals arepermitted to consume the usual diet. Alternatively, such concentratedsupplements may be added directly to the feed to produce a nutritionallybalanced, finished feed containing a therapeutically effective level ofa compound of the present invention. The mixtures are thoroughly blendedby standard procedures, such as in a twin shell blender, to ensurehomogeneity.

[0194] If the supplement is used as a top dressing for the feed, itlikewise helps to ensure uniformity of distribution of the compoundacross the top of the dressed feed.

[0195] Drinking water and feed effective for increasing lean meatdeposition and for improving lean meat to fat ratio are generallyprepared by mixing a compound of the present invention with a sufficientamount of animal feed to provide from about 10⁻³ to about 500 ppm of thecompound in the feed or water.

[0196] The preferred medicated swine, cattle, sheep and goat feedgenerally contain from about 1 to about 400 grams of a compound of thepresent invention (or combination) per ton of feed, the optimum amountfor these animals usually being about 50 to about 300 grams per ton offeed.

[0197] The preferred poultry and domestic pet feeds usually containabout 1 to about 400 grams and preferably about 10 to about 400 grams ofa compound of the present invention (or combination) per ton of feed.

[0198] For parenteral administration in animals, the compounds of thepresent invention (or combination) may be prepared in the form of apaste or a pellet and administered as an implant, usually under the skinof the head or ear of the animal in which increase in lean meatdeposition and improvement in lean meat to fat ratio is sought.

[0199] In general, parenteral administration involves injection of asufficient amount of a compound of the present invention (orcombination) to provide the animal with about 0.01 to about 20 mg/kg/dayof body weight of the drug. The preferred dosage for poultry, swine,cattle, sheep, goats and domestic pets is in the range of from about0.05 to about 10 mg/kg/day of body weight of drug.

[0200] Paste formulations can be prepared by dispersing the drug in apharmaceutically acceptable oil such as peanut oil, sesame oil, corn oilor the like.

[0201] Pellets containing an effective amount of a compound of thepresent invention, pharmaceutical composition, or combination can beprepared by admixing a compound of the present invention or combinationwith a diluent such as carbowax, carnuba wax, and the like, and alubricant, such as magnesium or calcium stearate, can be added toimprove the pelleting process.

[0202] It is, of course, recognized that more than one pellet may beadministered to an animal to achieve the desired dose level which willprovide the increase in lean meat deposition and improvement in leanmeat to fat ratio desired. Moreover, implants may also be madeperiodically during the animal treatment period in order to maintain theproper drug level in the animal's body.

[0203] The present invention has several advantageous veterinaryfeatures. For the pet owner or veterinarian who wishes to increaseleanness and/or trim unwanted fat from pet animals, the instantinvention provides the means by which this may be accomplished. Forpoultry, beef and swine breeders, utilization of the method of thepresent invention yields leaner animals that command higher sale pricesfrom the meat industry.

[0204] Embodiments of the present invention are illustrated by thefollowing Examples. It is to be understood, however, that theembodiments of the invention are not limited to the specific details ofthese Examples, as other variations thereof will be known, or apparentin light of the instant disclosure, to one of ordinary skill in the art.

EXAMPLES

[0205] Unless specified otherwise, starting materials are generallyavailable from commercial sources such as Aldrich Chemicals Co.(Milwaukee, Wis.), Lancaster Synthesis, Inc. (Windham, N.H.), AcrosOrganics (Fairlawn, N.J.), Maybridge Chemical Company, Ltd. (Cornwall,England), Tyger Scientific (Princeton, N.J.), and AstraZenecaPharmaceuticals (London, England).

[0206] The acronyms listed below have the following correspondingmeanings:

[0207] LiN(TMS)₂—lithium hexamethyldisilazide

[0208] PS-DIEA—polystyrene-bound diisopropylethylamine (available fromArgonaut Technologies, Foster City, Calif.)

General Experimental Procedures

[0209] NMR spectra were recorded on a Varian Unity™ 400 or 500(available from Varian Inc., Palo Alto, Calif.) at room temperature at400 and 500 MHz ¹H, respectively. Chemical shifts are expressed in partsper million (6) relative to residual solvent as an internal reference.The peak shapes are denoted as follows: s, singlet; d, doublet; t,triplet; q, quartet; m, multiplet; br s, broad singlet; v br s, verybroad singlet; br m, broad multiplet; 2s, two singlets. In some casesonly representative ¹H NMR peaks are given.

[0210] Mass spectra were recorded by direct flow analysis using positiveand negative atmospheric pressure chemical ionization (APcl) scan modes.A Waters APcl/MS model ZMD mass spectrometer equipped with Gilson 215liquid handling system was used to carry out the experiments

[0211] Mass spectrometry analysis was also obtained by RP-HPLC gradientmethod for chromatographic separation. Molecular weight identificationwas recorded by positive and negative electrospray ionization (ESI) scanmodes. A Waters/Micromass ESI/MS model ZMD or LCZ mass spectrometerequipped with Gilson 215 liquid handling system and HP 1100 DAD was usedto carry out the experiments.

[0212] Where the intensity of chlorine or bromine-containing ions aredescribed, the expected intensity ratio was observed (approximately 3:1for ³⁵Cl/³⁷Cl-containing ions and 1:1 for ⁷⁹Br/⁶¹Br-containing ions) andonly the lower mass ion is given. MS peaks are reported for allexamples.

[0213] Optical rotations were determined on a PerkinElmer™ 241polarimeter (available from PerkinElmer Inc., Wellesley, Mass.) usingthe sodium D line (λ=589 nm) at the indicated temperature and arereported as follows [α]_(D) ^(temp), concentration (c=g/100 ml), andsolvent.

[0214] Column chromatography was performed with either Baker™ silica gel(40 μm; J. T. Baker, Phillipsburg, N.J.) or Silica Gel 50 (EM Sciences™,Gibbstown, N.J.) in glass columns or in Biotage™ columns (ISC, Inc.,Shelton, Conn.) under low nitrogen pressure. Radial chromatography wasperformed using a Chromatotron™ (Harrison Research).

Preparation of Key Intermediates

[0215] Preparation of Intermediate5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid(2,2-diethoxyethyl)-amide (I-1A-1a):

[0216] To a stirred solution of5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid(prepared according to the methods described by Barth, et al. in U.S.Pat. No. 5,624,941); 740 mg, 2.01 mmol) andN-benzyl-N-(2,2-diethoxyethyl)amine (450 mg, 2.01 mmol) in methylenechloride (6.5 ml) at room temperature was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (464 mg,2.42 mmol) and then diisopropylethylamine (0.42 ml, 2.2 mmol), dropwise.After stirring for 23 hours, the reaction mixture was concentrated, invacuo, and then extracted from saturated aqueous sodium bicarbonate withethyl acetate. The combined organic layers were washed with brine, dried(MgSO₄), and concentrated, in vacuo. The crude material (1.05 g) waspurified on a Biotage™ Flash 40S column using 0-20% ethyl acetate inhexanes as eluant to afford I-1A-1a as a foam (534 mg, 46%): +ESI MS(M+1) 572.1; ¹H NMR (500 MHz, CD₂Cl₂) 1:1 mixture of rotamers, δ 7.51(br s, 0.5H), 7.47 (d, J=2.1 Hz, 0.5H), 7.38-7.34 (m, 2H), 7.38-7.23 (m,9H), 7.18-7.11 (m, 2H), 7.03 (s, 0.5H), 6.95 (s, 0.5H), 5.22 (s, 1H),4.91 (s, 1H), 4.83-4.79 (m, 1H), 3.56-3.07 (m, 6H), 1.20 (t, J=7.0 Hz,3H), 1.07 (t, J=7.0 Hz, 3H).

[0217] Preparation of Intermediate6-Benzyl-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2,6-dihydropyrazolo[3,4-c]pyridin-7-one(I-1A-1b):

[0218] A mixture of5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid(2,2-diethoxyethyl)-amide (I-1A-1a; 528 mg, 0.92 mmol) andp-toluenesulfonic acid monohydrate (175 mg, 0.92 mmol) in toluene (5 ml)was heated to reflux in round bottom flask fitted with a Dean-Starkcondenser. After 1 hour, the reaction mixture was cooled to roomtemperature, and then extracted from saturated aqueous sodiumbicarbonate with ethyl acetate. The combined organic layers were washedwith brine, dried (MgSO₄), and concentrated in vacuo. The crude material(0.49 g) was purified on a Biotage™ Flash 40S column using 10-20-40%ethyl acetate in hexanes as eluant to afford I-1A-1b as a solid (69 mg,16%): +ESI MS (M+1) 480.1; ¹H NMR (500 MHz, CD₂Cl₂) δ 7.50 (d, J=1.5 Hz,1H), 7.48 (d, J=8.3 Hz, 1H), 7.42 (dd, J=8.3, 2.1 Hz, 1H), 7.38-7.27 (m,7H), 7.18 (d, J=8.7 Hz, 2H), 6.95 (d, J=7.5 Hz, 1H), 6.42 (d, J=7.5 Hz,1H), 5.21 (s, 2H).

[0219] Preparation of Intermediate7-Chloro-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[3,4-c]pyridine(I-1A-1c):

[0220] A stirred suspension of6-benzyl-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2,6-dihydropyrazolo[3,4-c]pyridin-7-one(I-1A-1b; 153 mg, 0.32 mmol) in POCl₃ (3.5 ml) was heated to reflux for48 hr. After the reaction was cooled and concentrated, in vacuo, anethyl acetate solution of the residue was washed with saturated aqueousNaHCO₃ and then brine. The solution was dried (Na₂SO₄), concentrated, invacuo, and then purified on a Biotage™ Flash 12M column using 0-15-30%ethyl acetate in hexanes to afford I-1A-1c as an off-white solid (75 mg,58%): +ESI MS (M+1) 408.0; ¹H NMR (400 MHz, CD₂Cl₂) δ 8.01 (d, J=5.8 Hz,1H), 7.57-7.53 (m, 3H), 7.47 (dd, J=8.7, 2.1 Hz, 1H), 7.41 (d, J=8.7 Hz,2H), 7.27 (d, J=8.7 Hz, 2H).

[0221] Preparation of Intermediate1-Benzyl-4-ethylaminopiperidine-4-carbonitrile (I-1A-1d).,

[0222] To a solution of 4-N-benzylpiperidone (5.69 g, 29.5 mmol) inethanol (4.2 ml) cooled in an ice bath was added ethylaminehydrochloride (2.69 g, 32.3 mmol) in water (3 ml), keeping the internaltemperature of the reaction below 10° C. A solution of KCN (2.04 g, 31.3mmol) in water (7 ml) was added to the reaction solution over 10 minuteswhile keeping the internal temperature below 10° C. The reaction mixturewas then warmed to room temperature and stirred 18 hours. Isopropanol(10 ml) was added to the reaction mixture to give two distinct layers:lower colorless aqueous layer and orange organic upper layer. Theorganic layer was separated and stirred with water (30 ml) for 30minutes. The organic layer was separated (orange organic layer now thebottom layer), the solvent was removed in vacuo, and the resultant oildiluted in methylene chloride (30 ml). The organic layer was washed withbrine, dried (Na₂SO₄), filtered and concentrated, in vacuo, to giveI-1A-1d as an orange oil (6.05 g, 84%): +APcl MS (M+1) 244.2; ¹H NMR(400 MHz, CD₂Cl₂) δ 7.32 (d, J=4.1 Hz, 4H), 7.29-7.23 (m, 1H), 3.54 (s,2H), 2.81-2.76 (m, 2H), 2.75 (q, J=7.1 Hz, 2H), 2.35-2.29 (m, 2H),2.01-1.98 (m, 2H), 1.74-1.68 (m, 2H), 1.14 (t, J=7.1 Hz, 3H).

[0223] Preparation of Intermediate1-Benzyl-4-ethylaminopiperidine-4-carboxylic Acid Amide (I-1A-1e):

[0224] A solution of 1-benzyl-4-ethylaminopiperidine-4-carbonitrileI-1A-1d (0.58 g, 2.38 mmol) in methylene chloride (2 ml) cooled in anice bath was treated with H₂SO₄ (1.8 ml, 33 mmol), dropwise, whilekeeping the internal temperature below 20° C. The reaction mixture wasthen warmed to room temperature and stirred for 19 hours. After stirringwas discontinued, the thick pale orange H₂SO₄ bottom layer wasseparated, cooled in an ice bath, and then carefully quenched withconcentrated NH₄OH keeping the internal temperature below 55° C. Theaqueous layer was extracted with methylene chloride (2×10 ml), thecombined organic layers were washed with brine (20 ml), dried (Na₂SO₄),and then concentrated, in vacuo, to afford I-1A-1e as a pale orange oilthat solidified to a peach colored solid upon standing (0.54 g, 87%):+APcl MS (M+1) 262.2; ¹H NMR (400 MHz, CD₂Cl₂) δ 7.34-7.30 (m, 4H),7.29-7.21 (m, 1H), 7.16 (br s, 1H), 3.48 (s, 2H), 2.71-2.68 (m, 2H),2.47 (q, J=7.0 Hz, 2H), 2.17-2.02 (m, 4H), 1.62-1.58 (m, 2H), 1.41 (brs, 1H), 1.09 (t, J=7.0 Hz, 3H).

[0225] Preparation of Intermediate 4-Ethylaminopiperidine-4-carboxylicAcid Amide (I-1A-1f):

[0226] To a solution of 1-benzyl-4-ethylaminopiperidine-4-carboxylicacid amide (I-1A-1e; 7.39 g, 28.3 mmol) in methanol (100 ml) was added20% Pd(OH)₂ on carbon (50% water; 1.48 g). The mixture was placed on aParr® shaker and was reduced (50 psi H₂) at room temperature overnight.The mixture was filtered through a pad of Celite®, and then concentratedto give a colorless solid I-1A-if (4.84 g, quantitative): +APcl MS (M+1)172.2; ¹H NMR (400 MHz, CD₂Cl₂) δ 2.89 (ddd, J=12.9, 8.7, 3.3 Hz, 2H),2.75 (ddd, J=12.9, 6.6, 3.7 Hz, 2H), 2.45 (q, J=7.2 Hz, 2H), 1.95 (ddd,J=13.7, 8.3, 3.7 Hz, 2H), 1.55 (ddd, J=13.7, 6.6, 3.3 Hz, 2 h), 1.08 (t,J=7.1 Hz, 3H).

[0227] Preparation of Intermediate7-Chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[3,4-c]pyridine(I-1A-6a):

[0228] Intermediate I-1A-6a was prepared by procedures analogous tothose described above for the preparation of7-chloro-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[3,4-c]pyridine(I-1A-1c) using appropriate starting materials: +ESI MS (M+1) 374.3; ¹HNMR (400 MHz, CD₂Cl₂) δ 8.00 (d, J=6.2 Hz, 1H), 7.60-7.45 (m, 5H), 7.38(d, J=8.7 Hz, 2H), 7.27 (d, J=8.7 Hz, 2H).

[0229] Preparation of Intermediate1-Benzhydryl-3-ethylaminoazetidine-3-carboxylic Acid Amide (I-1A-6b):

[0230] Oxalyl chloride (145.2 g, 1.121 mol) was added to dichloromethane(3.75 liters) and the resulting solution was cooled to −78° C. Dimethylsulfoxide (179.1 g, 2.269 mol) was then added over a duration of 20minutes while maintaining internal temperature of the reaction below−70° C. during addition. 1-Benzhydrylazetidin-3-ol (250.0 g, 1.045 mol)was then added as a solution in dichloromethane (1.25 liter) to the−780C solution of DMSO/oxalyl chloride over a duration of 40 minutes(note—internal temperature maintained below −70° C. during addition).The solution was stirred for 1 hour at −78° C. followed by the additionof triethylamine (427.1 g, 4.179 mol) over 30 minutes (maintainedinternal temperature below −70° C. during addition). The reactionmixture was then allowed to come to room temperature slowly and stir for20 hours. 1.0 M hydrochloric acid (3.2 liters, 3.2 mol) was added to thecrude reaction solution over 30 minutes, followed by stirring for 10minutes at room temperature. The heavy dichloromethane layer (clearyellow in color) was then separated and discarded. The remaining acidicaqueous phase (clear, colorless) was treated with 50% sodium hydroxide(150 ml, 2.1 mol) with stirring over a 30-minute period. The finalaqueous solution had a pH=9. At this pH, the desired productprecipitated from solution as a colorless solid. The pH=9 solution wasstirred for 30 minutes and then the precipitated product was collectedby filtration. The collected solid was washed with 1.0 liter of waterand then air dried for 36 hr to give 1-benzhydrylazetidin-3-one (184.1g, 74%) as an off-white solid: +ESI MS (M+1 of hydrated ketone) 256.3;¹H NMR (400 MHz, CD₂Cl₂) δ 7.47-7.49 (m, 4H), 7.27-7.30 (m, 4H),7.18-7.22 (m, 2H), 4.60 (s, 1H), 3.97 (s, 4H).

[0231] To a solution of 1-benzhydrylazetidin-3-one (53.4 g, 225 mmol) inmethanol (750 ml) was added ethylamine hydrochloride (20.2 g, 243 mmol),KCN (15.4 g, 229 mmol) and then acetic acid (14.3 ml, 247 mmol) at roomtemperature. After stirring for 2.5 hours at room temperature, at whichpoint the starting ketone had been consumed, the mixture was heated at55° C. for 15 hours. The reaction mixture was cooled to 50° C. andtreated with dimethyl sulfoxide (19.2 ml, 270 mmol) and then 2N aqueousNaOH (251 ml) over a 10-minute period. A solution of 11% aqueousperoxide (80 ml, 247 mmol) was added over 5 minutes (exothermicreaction), during which time a precipitate formed. Additional water (270ml) was added to aid stirring. After the solution was cooled to roomtemperature and stirred for an additional hour, a solid precipitated outof solution and was collected on a sintered funnel, washed with water,and then dried, in vacuo, to give crude I-1A-6b (55.3 g, 79%) as asolid.

[0232] For purification purposes, crude1-benzhydryl-3-ethylaminoazetidine-3-carboxylic acid amide (I-2A-1f;83.0 g, 268 mmol) was added to 1 M HCl (1.3 l), portionwise. Afterwashing the solution with methylene chloride (1 liter, then 0.8 liter),the mixture was treated with 50% aqueous NaOH (130 ml) to bring thepH=10. The precipitate that formed on basification was collected on asintered funnel, washed with water, and then dried, in vacuo, to giveI-1A-6b (72.9 g, 88%) as a colorless solid: +ESI MS (M+1) 310.5; ¹H NMR(400 MHz, CD₃OD) δ 7.41 (d, J=7.1 Hz, 4H), 7.25 (t, J=7.5 Hz, 4H), 7.16(t, J=7.5 Hz, 2H), 4.49 (s, 1H), 3.44 (d, J=8.3 Hz, 2H), 3.11 (d, J=8.3Hz, 2H), 2.47 (q, J=7.1 Hz, 2H), 1.10 (t, J=7.3 Hz, 3H).

[0233] Preparation of Intermediate 3-Ethylaminoazetidine-3-carboxylicAcid Amide, Hydrochloride Salt (I-1A-6c):

[0234] To a suspension of1-benzhydryl-3-ethylaminoazetidine-3-carboxylic acid amide (I-1A-6b;36.1 g, 117 mmol) in methanol (560 ml) at room temperature was addedconcentrated aqueous HCl (19.5 ml, 234 mmol), resulting in a clearsolution. To 20% Pd(OH)₂ on carbon (3.75 g) was added methanol (85 ml),followed by the methanolic solution of I-1A-6b. The mixture was placedon a Parr® shaker and then reduced (50 psi H₂) at room temperature for20 hours. The reaction was then filtered through Celite® andconcentrated to a fraction of the original volume under reducedpressure, at which point a precipitate formed. The suspension wasdiluted with t-butylmethyl ether (MTBE; 500 ml), stirred for anadditional hour, and the precipitate collected by vacuum filtration. Thesolid was washed with MTBE and then dried, in vacuo, to afford I-1A-6c(24.8 g, 98%) as a colorless solid: +APcl MS (M+1) 144.1; ¹H NMR (400MHz, CD₂Cl₂) δ 4.56 (br s, 4H), 3.00 (q, J=7.2 Hz, 2H), 1.36 (t, J=7.1Hz, 3H).

[0235] Preparation of Intermediate4-amino-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylicacid ethyl ester (I-2A-1a):

[0236] To a solution of LiN(TMS)₂ (1.0 M in THF, 100 ml, 100 mmol) in400 ml diethyl ether at −78° C. under nitrogen,1-(4-chlorophenyl)ethanone (14.3 ml, 110 mmol) in ether (80 ml) wasadded, dropwise, via addition funnel. After the addition was complete,the reaction mixture was stirred at −78° C. for 40 minutes. Oxalic aciddiethyl ester (14.3 ml, 105 mmol) was added in one portion via syringe.The reaction mixture was warmed to room temperature and stirredovernight. The pale white precipitate that formed was collected byfiltration. The solid was dried in vacuo to give4-(4-chlorophenyl)-2-hydroxy-4-oxobut-2-enoic acid ethyl ester lithiumsalt (24.0 g, 92%).

[0237] 4-(4-Chlorophenyl)-2-hydroxy-4-oxobut-2-enoic acid ethyl esterlithium salt (10 g, 38.37 mmol) was dissolved in acetic acid (400 ml).After the solution was cooled to 10° C. with an ice-water bath, aconcentrated aqueous solution of sodium nitrite (2.86 g, 40.29 mmol) wasadded dropwise, keeping the temperature between 10 and 15° C. Thereaction mixture was stirred for another 45 minutes, and2-chlorophenylhydrazine HCl salt (8.5 g, 46.04 mmol) was added inportions. Stirring was continued for 3 hours. Upon completion of thereaction, the reaction mixture was poured into 600 ml ice-cold water. Ayellow solid precipitated and after 2 hours, it was collected, washedwith water, and dried to give crude4-(4-chlorophenyl)-2-[(2-chlorophenyl)hydrazono]-3-nitroso-4-oxobutyricacid ethyl ester which was used in the next step without furtherpurification.

[0238] The yellow solid obtained from last step was redissolved intoisopropanol and concentrated H₂SO₄ (1 ml) was added. The reactionmixture was heated to 60° C. for 3 hours. After cooling to roomtemperature, the reaction mixture was poured into ice/saturated aqueousNaHCO₃. The precipitate was formed and collected by filtration and driedto give1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-nitroso-1H-pyrazole-3-carboxylicacid ethyl ester. It was used in the next step without furtherpurification.

[0239]1-(2-Chlorophenyl)-5-(4-chlorophenyl)₄-nitroso-1H-pyrazole-3-carboxylicacid ethyl ester obtained from the last step was dissolved in ethylacetate (200 ml) and water (200 ml). Sodium dithionite was added untilthe disappearance of1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-nitroso-1H-pyrazole-3-carboxylicacid ethyl ester was confirmed by TLC (ethyl acetate/hexane, 50/50). Theorganic layer was separated and the aqueous layer was extracted withethyl acetate. The combined organic layers were dried over magnesiumsulfate and the solvent was removed, in vacuo. The red solid obtainedwas further purified by plug filtration (silica, ethyl acetate/hexane,50/50) to give4-amino-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylicacid ethyl ester I-2A-1a (21.86 g, 76%). MS: 376.1 (M+1)⁺.

[0240] Preparation of Intermediate3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ol(I-2A-1b):

[0241] A mixture of4-amino-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylicacid ethyl ester I-2A-1a (19.27 g, 51.2 mmol) and formamidine acetate(15.99g, 153.6 mmol) in 2-ethoxyethanol (100 ml) was refluxed for 3.5 hunder nitrogen. The reaction mixture was then cooled to room temperatureand poured into ice-cold water. The yellow precipitate that formed wascollected by filtration and washed with water. The solid was stirred in45 ml methyl tert-butyl ether for 30 minutes. Cyclohexane (90 ml) wasadded, and the stirring was continued for another 45 minutes. The paleyellow solid was collected by filtration and dried to give3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ol1-2A-1 b (17.55 g, 87%): MS: 357.1 (M+1)⁺.

[0242] Preparation of Intermediate7-Chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine(I-2A-1c):

[0243] To a suspension of3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-olI-2A-1 b (17.55 g, 49.1 mmol) in 1,2-dichloroethane (109 ml) was addedN,N-diethylaniline (32.8 ml, 206.22 mmol) followed by POCl₃ (70 ml, 0.7M). The reaction mixture was heated to reflux under nitrogen for 3hours, and cooled to room temperature. The solvent was removed underreduced pressure. Excess POCl₃ was removed by co-evaporation withtoluene three times. The residue was dissolved in methylene chloride andslowly poured into vigorously stirred 1:1 CH₂Cl₂/saturated aqueousNaHCO₃ (500 ml). Additional saturated aqueous NaHCO₃ was added until thepH of the mixture was adjusted to neutral. The organic layer wasseparated and the aqueous layer was extracted with 200 ml methylenechloride three times. The organic layers were combined, dried (MgSO₄),and concentrated. The residue was purified by SiO2-gel chromatographyusing 100% CH₂Cl₂ as the eluant to give7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidineI-2A-1c (18.4 g, 76%): MS: 375.0 (M+1)⁺.

[0244] Preparation of Intermediate1-Benzhydryl-3-methylaminoazetidine-3-carbonitrile (I-2A-69a):

[0245] To a solution of 1-benzhydrylazetidin-3-one (2.13 g, 8.98 mmol)in methanol (17 ml) was added methylamine hydrochloride (1.21 g, 18.0mmol) and then acetic acid (1.03 ml, 18.0 mmol) at room temperature.After stirring for 5 minutes, solid KCN (1.17 g, 18.0 mmol) was addedand the mixture was heated to 60° C. for 19 hours. The reaction wascooled; the solid product was collected by vacuum filtration, rinsedwith methanol, and then dried, in vacuo, to afford I-2A-69a as acolorless solid (2.50 g, quantitative): +ESI MS (M+1) 278.3; ¹H NMR (400MHz, CD₂Cl₂) δ 7.43 (d, J=7.5 Hz, 4H), 7.29 (t, J=7.5 Hz, 4H), 7.23 (t,J=7.3 Hz, 2H), 4.45 (s, 1H), 3.55 (d, J=7.5 Hz, 2H), 3.15 (d, J=7.1 Hz,2H), 2.40 (s, 3H).

[0246] Preparation of Intermediate1-Benzhydryl-3-methylaminoazetidine-3-carboxylic Acid Amide (I-2A-69b):

[0247] A vigorously stirred solution of1-benzhydryl-3-methylaminoazetidine-3-carbonitrile (I-2A-69a; 2.10 g,7.57 mmol) in methylene chloride (25 ml) cooled in an ice bath wastreated with H₂SO₄ (4.0 ml, 76 mmol), dropwise. After the reactionmixture was allowed to warm to room temperature and stir overnight, itwas cooled in an ice bath and then carefully quenched with concentratedNH₄OH to pH 11. The mixture was extracted with methylene chloride, thecombined organic layers were dried (Na₂SO₄) and then concentrated, invacuo, to afford I-2A-69b (1.2 g, 54%) as an off-white solid: +ESI MS(M+1) 296.3; ¹H NMR (400 MHz, CD₃OD) δ 7.41 (d, J=7.5 Hz, 4H), 7.25 (t,J=7.5 Hz, 4H), 7.16 (t, J=7.1 Hz, 2H), 4.48 (s, 1H), 3.41 (d, J=8.7 Hz,2H), 3.09 (d, J=8.7 Hz, 2H), 2.24 (s, 3H).

[0248] Preparation of Intermediate2-Benzhydryl-5-methyl-2,5,7-triazaspiro[3,4]oct-6-en-8-one (I-2A-69c):

[0249] N,N-Dimethylformamide dimethyl acetal (1.1 ml, 8.3 mmol) wascombined with 1-benzhydryl-3-methylaminoazetidine-3-carboxylic acidamide (I-2A-69b; 153 mg, 0.52 mmol) and heated to reflux. After 3 hours,the suspension was cooled and extracted from saturated aqueous NaHCO₃with ethyl acetate. The combined extracts were dried (Na₂SO₄), andconcentrated, in vacuo, to afford I-2A-69c as a solid (152 mg, 96%):+ESI MS (M+1) 306.3; ¹H NMR (400 MHz, CD₃OD) δ 8.42 (s, 1H), 7.47 (d,J=7.5 Hz, 4H), 7.27 (t, J=7.5 Hz, 4H), 7.17 (t, J=7.5 Hz, 2H), 4.57 (s,1H), 3.58 (s, 3H), 3.55 (d, J=10.0 Hz, 2H), 3.34 (d, J=10.0 Hz, 2H).

[0250] Preparation of Intermediate5-Methyl-2,5,7-triazaspiro[3.4]octan-8-one. Hydrochloride Salt(I-2A-69d):

[0251] To a solution of2-benzhydryl-5-methyl-2,5,7-triazaspiro[3.4]oct-6-en-8-one (I-2A-69c;189 mg, 0.619 mmol) in methanol (30 ml) was added 1 M HCl in diethylether (1.3 ml). After the addition of 20% Pd(OH)₂ on carbon (50% water;95 mg), the mixture was placed on a Parr® shaker and then reduced (50psi H₂) at room temperature for 5 hours. The reaction mixture wasfiltered through a 0.45 PM disk, and then concentrated, in vacuo, togive a solid. Trituration from diethyl ether afforded I-2A-69d (124 mg,94%) as an off-white solid: +APcl MS (M+1) 142.0; ¹H NMR (400 MHz,CD₃OD) δ 4.38 (d, J=12.0 Hz, 2H), 4.17 (s, 2H), 4.13 (d, J=12.5 Hz, 2H),2.71 (s, 3H).

[0252] Preparation of Intermediate 3-Methylaminoazetidine-3-carboxylicAcid Amide. Hydrochloride Salt (I-2A-90a):

[0253] To a suspension of1-benzhydryl-3-methylaminoazetidine-3-carboxylic acid amide (I-2A-69b;13.5 g, 45.8 mmol) in methanol (90 ml) was added concentrated aqueousHCl (8.0 ml, 96 mol), dropwise, to give a homogeneous solution. Afterthe addition of 20% Pd(OH)₂ on carbon (50% water; 4.1 g), the mixturewas placed on a Parr® shaker and then reduced (50 psi H₂) at roomtemperature for 7 hours. The mixture was filtered through a pad ofCelite®, washing with a copious amount of 9:1 methanol/water, and then9:1 tetrahydrofuran/water until no product eluted (determined withninhydrin stain). The filtrate was then concentrated, in vacuo, and theresidue was then triturated from diethyl ether to give I-2A-90a (9.3 g,quantitative) as a brown solid: +APcl MS (M+1) 129.9; ¹H NMR (400 MHz,CD₃OD) δ 4.50 (d, J=12.0 Hz, 2H), 4.43 (d, J=12.9 Hz, 2H), 2.64 (s, 3H).

[0254] Preparation of Intermediate1-Benzhydryl-3-benzylaminoazetidine-3-carbonitrile (I-3A-50a):

[0255] To a solution of 1-benzhydrylazetidin-3-one (3.3 g, 14 mmol) inmethanol (35 ml) was added benzylamine (1.6 ml, 15 mmol) and then aceticacid (0.88 ml, 15 mmol) at room temperature. After stirring for 45minutes, solid NaCN (0.76 g, 15 mmol) was added in portions over 2minutes and the mixture was heated to reflux overnight. The reaction,which now contained a precipitate, was cooled and then stirred at roomtemperature. The solids were collected by vacuum filtration, rinsed witha small volume of cold methanol, and then dried, in vacuo, to giveI-3A-50a as a solid (3.56 g, 72%): +APcl MS (M+1) 354.4; ¹H NMR (400MHz, CD₃OD) δ 7.40 (d, J=7.5 Hz, 4H), 7.35 (d, J=7.5 Hz, 2H), 7.31-7.20(m, 7H), 7.16 (t, J=7.3 Hz, 2H), 4.44 (s, 1H), 3.76 (s, 2H), 3.48 (d,J=8.3 Hz, 2H), 3.05 (d, J=8.3 Hz, 2H).

[0256] Preparation of Intermediate1-Benzhydryl-3-benzylaminoazetidine-3-carboxylic Acid Amide (I-3A-50b):

[0257] A solution of 1-benzhydryl-3-benzylaminoazetidine-3-carbonitrileI-3A-50a (3.45 g, 9.76 mmol) in methylene chloride (55 ml) cooled in anice bath was treated with H₂SO₄ (8.1 ml, 0.15 mol), dropwise. After thereaction mixture was allowed to warm to room temperature and stirovernight, it was cooled in an ice bath and then carefully quenched withconcentrated NH₄OH to pH 10. The mixture was extracted with methylenechloride; the combined organic layers were washed with brine, dried(Na₂SO₄), and then concentrated, in vacuo, to afford a brown solid.Trituration of this material from hexanes/diethyl ether afforded a lighttan solid which was collected by vacuum filtration, washed withadditional hexanes and dried, in vacuo, to give I-3A-50b (3.34 g, 92%):+ESI MS (M+1) 372.4; ¹H NMR (400 MHz, CD₃OD) δ 7.41 (d, J=7.5 Hz, 4H),7.35 (d, J=7.5 Hz, 2H), 7.31-7.22 (m, 7H), 7.16 (t, J=7.7 Hz, 2H), 4.50(s, 1H), 3.60 (s, 2H), 3.48 (d, J=8.3 Hz, 2H), 3.16 (d, J=8.3 Hz, 2H).

[0258] Preparation of Intermediate2-Benzhydryl-5-benzyl-2,5,7-triazaspiro[3.4]oct-6-en-8-one (I-3A-50c):

[0259] N,N-Dimethylformamide dimethyl acetal (16 ml, 121 mmol) wascombined with 1-benzhydryl-3-benzylaminoazetidine-3-carboxylic acidamide (I-3A-50b; 3.03 g, 8.16 mmol) and heated to reflux. After 4 hours,the suspension was cooled and extracted from saturated aqueous NaHCO₃with ethyl acetate. The combined extracts were dried (Na₂SO₄) andconcentrated, in vacuo, to give a crude solid (3.50 g). Purification ofthe residue on a Biotage™ Flash 40M column using 0-3% methanol inmethylene chloride as eluant afforded I-3A-50c as a yellowish solid(1.92 g, 62%): +ESI MS (M+1) 382.3; ¹H NMR (400 MHz, CD₃OD) δ 8.66 (s,1H), 7.59 (d, J=7.1 Hz, 2H), 7.49-7.11 (m, 13H), 5.12 (s, 2H), 4.44 (s,1H), 3.31 (d, J=9.6 Hz, 2H), 3.20 (d, J=9.6 Hz, 2H).

[0260] Preparation of Intermediate 2,5,7-Triazaspiro[3.4]octan-8-one,Hydrochloride Salt (I-3A-50d):

[0261] To a solution of2-benzhydryl-5-benzyl-2,5,7-triazaspiro[3.4]oct-6-en-8-one (I-3A-50c;1.83 g, 4.80 mmol) in methanol/methylene chloride was added excess 1 MHCl in diethyl ether (10 ml). After stirring for 10 minutes, the solventwas removed, in vacuo, and the resultant hydrochloride salt wasdissolved in methanol (50 ml). After the addition of 20% Pd(OH)₂ oncarbon (50% water; 1.1 g), the mixture was placed on a Parr® shaker andthen reduced (50 psi H₂) at room temperature for 22 hours. The reactionwas filtered through a 0.45 μM disk, and then concentrated, in vacuo, togive a gummy solid. This material was triturated from methanol to affordI-3A-50d (450 mg, 47%) as a tan solid: +APcl MS (M+1) 127.9; ¹H NMR (400MHz, CD₃OD) δ 4.51 (s, 2H), 4.41-4.33 (m, 4H).

[0262] Preparation of Intermediate3-(4-Chlorophenyl)-2-(2-chlorophenyl)-5-ethyl-2H-pyrazolo[4,3-d]pyrimidin-7-ol(I-10A-1a):

[0263] Potassium t-butoxide (3.0 ml, 1 M in THF; 3.0 mmol) was added toa suspension of propionamidine hydrochloride (326 mg; 3.0 mmol) inethoxyethanol (3 ml). The reaction mixture was immediately concentratedunder vacuum. The residue was re-suspended in ethoxyethanol (3 ml), and4-amino-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylicacid ethyl ester I-2A-1a (376 mg, 1 mmol) and glacial acetic acid (250μl; 4.4 mmol) were added. The resulting mixture was heated at 125° C.for 43 hours, cooled to room temperature, quenched with saturatedaqueous NaCl, and extracted with ethyl acetate (2×). The combinedorganic extracts were washed with 0.5 M citric acid, 1 M aqueous K₂CO₃,and saturated aqueous NaCl, dried, and concentrated in vacuo. Theresidue was purified by radial chromatography (4 mm silica gel plate;elution with CH₂Cl₂, followed by 50% hexane/ethyl acetate) to give thedesired product I-10A-1a (7 mg). A solid also precipitated out of thecombined aqueous layers and was collected by filtration to give, afterdrying overnight, additional product (15 mg): MS (M+1)⁺ 385.4; ¹H NMR(400 MHz, d₆-DMSO) δ 12.05 (s, 1H), 7.78-7.40 (dd, J=7.5, 1.4 Hz, 1H),7.67-7.53 (m, 3H), 7.47-7.42 (m, 2H), 7.39-7.34 (m, 2H), 2.59 (q, J=7.5Hz, 2H), 1.20 (t, J=7.5 Hz, 3H).

[0264] Preparation of Intermediate Benzoic Acid 2,2-Difluorobutyl ester(I-10A-6a):

[0265] To a solution of benzoic acid 2-oxobutyl ester (20 g, 104 mmol)in CH₂Cl₂ (40 ml) at room temperature was added (diethylamino)sulfurtrifluoride (DAST, 36.9 g, 30 ml, 228.9 mmol) and ethanol (0.4 ml). Thereaction mixture was stirred for 17 hours. Additional DAST (4.5 ml) wasadded dropwise, and the resulting mixture was stirred for 72 hours. Thereaction mixture was quenched first with cold water (250 ml) and thenwith cold saturated aqueous NaHCO₃ (100 ml). The organic layer wasseparated, and the aqueous phase was extracted with CH₂Cl₂ (2×). Thecombined extracts were dried and concentrated under vacuum. The cruderesidue was purified via silica gel chromatography using a solventgradient of 0-2% ethyl acetate/hexanes to give the desired product,benzoic acid 2,2-difluorobutyl ester (I-10A-6a), as a colorless oil: ¹HNMR (400 MHz, CDCl₃) δ 8.05 (d, J=1.2 Hz, 2H), 7.58 (m, 1H), 7.45 (m,2H), 4.48 (t, J=12.0 Hz, 2H), 2.04 (m, 2H), 1.08 (t, J=7.5 Hz, 3H).

[0266] Preparation of Intermediate 2,2-Difluorobutan-1-ol (I-10A-6b):

[0267] A solution of benzoic acid 2,2-difluorobutyl ester (I-10A-6a; 16g, 75 mmol) in 1:1.6 6N aqueous NaOH/methanol (65 ml) was stirred atambient temperature for 2 hours. The reaction mixture was concentratedunder vacuum to remove the methanolic solvent. The aqueous residue wasextracted with diethyl ether (2×) and the combined ether extracts weredried and concentrated to give the desired product,2,2-difluorobutan-1-ol (I-10A-6b), as a yellow oil contaminated withsome diethyl ether and methanol (6.5 g, 79%): ¹H NMR (400 MHz, CDCl₃) δ3.72 (t, 2H), 1.9 (m, 2H), 1.02 (t, 3H).

[0268] Preparation of Intermediate Trifluoromethanesulfonic Acid2,2-Difluorobutyl Ester (I-10A-6c):

[0269] A solution of 2,2-difluorobutan-1-ol (I-10A-6b; 1.00 g, 9.1mmol), N-phenyltrifluoromethanesulfonimide (4.87 g, 13.6 mmol), andtriethylamine (3 ml) in CH₂Cl₂ (15 ml) was stirred at ambienttemperature for 2 hours. The reaction mixture was quenched with 1 Naqueous NaOH and extracted with CH₂Cl₂ (3×). The combined organicextracts were washed with saturated aqueous NaCl, dried, andconcentrated under vacuum. The crude residue was purified via silica gelchromatography using a solvent gradient of 10-50% ethyl acetate/hexanesto give the product, trifluoromethanesulfonic acid 2,2-difluoro-butylester (I-10A-6c), as a colorless oil (0.70 g, 32%): ¹H NMR (400 MHz,CDCl₃) δ 4.5 (t, J=11.0 Hz, 2H), 1.95 (m, 2H), 1.08 (t, J=7.5 Hz, 3H).

[0270] Preparation of Intermediate Benzoic Acid 2,2-Difluoropropyl Ester(I-10A-7a):

[0271] The title compound 1-10A-7a (47.8 g, 94%) was prepared frombenzoic acid 2-oxopropyl ester (41.4 g, 232 mmol) using the proceduredescribed above for the preparation of I-10A-6a. The crude product wasused without further purification: ¹H NMR (400 MHz, CDCl₃) δ 8.05 (d,2H), 7.58 (m, 1H), 7.45 (m, 2H), 4.47 (t, J=12.0 Hz, 2H), 1.73 (t,J=18.7 Hz, 3H).

[0272] Preparation of Intermediate 2,2-Difluoropropan-1-ol (I-10A-7b):

[0273] A two-phase mixture of benzoic acid 2,2-difluoropropyl ester(I-10A-7a; 20 g, 100 mmol) in 1:1.5:2 6N NaOH/H₂O/diethyl ether (183 ml)was stirred at 500C for 17 hours. After cooling to ambient temperature,the reaction mixture was extracted with diethyl ether (3×), and thecombined extracts were dried and concentrated under reduced pressure.The orange-colored crude residue was distilled to give the desiredproduct, 2,2-difluoropropan-1-ol (I-10A-7b), as a colorless oil (2.8 g,29%): boiling point—100° C. (1 atm); ¹H NMR (400 MHz, CDCl₃) δ 3.71 (t,J=12.5 Hz, 2H), 1.64 (t, J=18.7 Hz, 3H).

[0274] Preparation of Intermediate Trifluoromethanesulfonic Acid2,2-Difluoropropyl Ester (I-10A-7c):

[0275] To a solution of 2,2-difluoropropan-1-ol (I-10A-7b; 1.76 g, 18.3mmol), dimethylaminopropylamine (DMAP: 157 mg, 1.3 mmol), andtriethylamine (2.20 g, 3.1 ml, 22 mmol) in CH₂Cl₂ (15 ml) at 0° C. wasadded triflic anhydride (Tf₂O; 6.2 g, 3.7 ml, 22 mmol). The reactionmixture initially turned a pink color, then a yellow color following thecomplete addition of Tf₂O. The reaction mixture was stirred at 0° C. for2 hours and diluted with CH₂Cl₂. The organic solution was washed withwater, 1 M aqueous citric acid, and saturated aqueous NaHCO₃, dried, andconcentrated under reduced pressure (225 mm/Hg; bath temperature −30°C.) to give the desired product, trifluoromethanesulfonic acid2,2-difluoropropyl ester (I-10A-7c), as a pink oil (3 g, 72%): ¹H NMR(400 MHz, CDCl₃) δ 4.49 (t, J=10.8 Hz, 2H), 1.74 (t, 3H).

[0276] Preparation of Intermediate3-(4-Chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[3,4-c]pyridin-7-ol(I-10A-14a):

[0277] A stirred mixture of7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[3,4-c]pyridine(I-1A-6a; 420 mg, 1.12 mmol) in 3M aqueous HCl (7.5 ml) andtetrahydrofuran (12 ml) was heated overnight at 45° C. The reactionmixture was cooled and the pH adjusted to 8 with 5M aqueous NaOH. Theaqueous layer was dried (Na₂SO₄), concentrated, in vacuo, and theresulting solid repulped from 40% ethyl acetate/isopropyl ether (20 ml)to afford I-10A-14a as an off-white solid (320 mg, 80%): +ESI MS (M+1)356.3; ¹H NMR (400 MHz, CD₂Cl₂) δ 9.64 (br s, 1H), 7.55-7.41 (m, 4H),7.34 (d, J=8.7 Hz, 2H), 7.21 (d, J=8.7 Hz, 2H), 6.96 (dd, J=7.5, 5.8 Hz,1H), 6.50 (d, J=7.5 Hz, 1H).

Example 1

[0278] Preparation of1-[3-(4-Chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[3,4-c]pyridin-7-yl]-4-ethylaminopiperidine-4-carboxylicAcid Amide (1A-1):

[0279]7-Chloro-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[3,4-c]pyridine(I-1A-1c; 71 mg, 0.17 mmol), 4-ethylaminopiperidine-4-carboxylic acidamide (I-1A-1f; 62 mg, 0.36 mmol) and triethylamine (52 microliters,0.52 mmol) were combined in ethanol (1.2 ml) and the heterogeneousmixture was stirred and heated to 60° C. After 3 days, the reaction wascooled to room temperature and purified on a Biotage™ Flash 12M columnusing a solvent gradient of 0-2-4-6% methanol in methylene chloride aseluant to afford title compound I-1A-1 (73 mg, 78%) as a glass: +ESI MS(M+1) 543.1; ¹H NMR (500 MHz, CD₃OD) δ 7.63 (d, J=2.1 Hz, 1H), 7.60 (d,J=8.7 Hz, 1H), 7.57 (d, J=6.2 Hz, 1H), 7.49 (dd, J=8.3, 2.1 Hz, 1H),7.38 (d, J=8.3 Hz, 2H), 7.26 (d, J=8.3 Hz, 2H), 6.84 (d, J=6.2 Hz, 1H),4.35-4.28 (m, 2H), 4.10 (ddd, J=13.3, 9.1, 3.3 Hz, 2H), 2.51 (q, J=7.1Hz, 2H), 2.12 (ddd, J=13.7, 9.1, 3.7 Hz, 2H), 1.73 (dq, J=13.3, 3.3 Hz,2H), 1.10 (t, J=7.1 Hz, 3H).

[0280] The hydrochloride salt of compound 1A-1 may be prepared using thefollowing procedure:

[0281] To a solution of1-[3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[3,4-c]pyridin-7-yl]-4-ethylaminopiperidine-4-carboxylicacid amide (I-1A-1; 69 mg, 0.13 mmol) in methylene chloride (3 ml) wasadded 1 M HCl in diethyl ether (0.32 ml), dropwise. A precipitate formedafter 3 minutes. After stirring for 10 minutes, the ether was removed,in vacuo, the solids were washed with diethyl ether and then dried, invacuo, to afford the hydrochloride salt of 1A-1 as an off-white solid(69 mg, 88%): ¹H NMR (500 MHz, CD₃OD) δ 7.74-7.70 (m, 2H), 7.59 (dd,J=8.7, 2.0 Hz, 1H), 7.48 (d, J=8.3 Hz, 2H), 7.40 (d, J=7.1 Hz, 1H), 7.35(d, J=8.7 Hz, 2H), 7.18 (d, J=7.1 Hz, 1H), 3.08 (q, J=7.2 Hz, 2H),2.76-2.66 (br m, 2H), 2.32 (ddd, J=14.1, 9.6, 4.1 Hz, 2H), 1.37 (t,J=7.3 Hz, 3H).

[0282] The compounds listed in Table 1 below were prepared usingprocedures analogous to those described above for the synthesis ofCompound 1A-1 using the appropriate starting materials which areavailable commercially, prepared using preparations well-known to thoseskilled in the art, or prepared in a manner analogous to routesdescribed above for other intermediates. The compounds listed below weregenerally isolated as their free base and then converted to theircorresponding hydrochloride salts prior to in vivo testing. TABLE I

Example No. —R^(0b) —NRR′ MS (M+H)⁺ 1A-2 —Cl

443.1 1A-3 —Cl

472.2 1A-4 —Cl

557.2 1A-5 —Cl

583.2 1A-6 —H

481.4 1A-7 —H

523.5

Example 2

[0283] Preparation of3-(4-Chlorophenyl)-2-(2-chlorophenyl)-7-pyrrolidin-1-yl-2H-pyrazolo[4,3-d]pyrimidine(2A-1):

[0284] To a suspension of7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidineI-2A-1c (40 mg, 0.1 mmol) in 5 ml ethanol was added pyrrolidine (711 mg,10 mmol). The reaction mixture was stirred at room temperature for 1hour and became homogeneous. After the reaction was complete (asmonitored by TLC, ethyl acetate/hexane, 50/50), ethanol was removedunder reduced pressure. The residue was redissolved in ethyl acetate,washed with water, dried over magnesium sulfate, and concentrated. Thecrude product was purified by HPLC to give3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-pyrrolidin-1-yl-2H-pyrazolo[4,3-d]pyrimidine2A-1 (17 mg, 38.2%). MS: 410.2 (M+1)⁺; ¹H NMR (400 MHz, CD₂Cl₂) δ 8.3(s, 1H), 7.5 (m, 6H), 7.3 (d, J=8.7 Hz, 2H), 4.2 (t, J=6.3 Hz, 2H), 3.8(t, J=7.1 Hz, 2H), 2.1 (m, 4H).

[0285] The compounds listed in Table 2 below were prepared usingprocedures analogous to those described above for the synthesis ofCompound 2A-1 using the appropriate starting materials which areavailable commercially, prepared using preparations well-known to thoseskilled in the art, or prepared in a manner analogous to routesdescribed above for other intermediates. The compounds listed below weregenerally isolated as their free base and then converted to theircorresponding hydrochloride salts prior to in vivo testing. TABLE 2

Example MS No. R^(0a) R^(0b) —NRR′ (M+H)⁺ 2A-2 Cl Cl —N(CH₂CH₃)₂ 448.22A-3 Cl Cl

458.1 2A-4 Cl Cl

460.1 2A-5 Cl Cl

473.2 2A-6 Cl Cl

484.2 2A-7 Cl Cl

446.1 2A-8 Cl H

424.2 2A-9 Cl H

426.2 2A-10 Cl H

439.2 2A-11 Cl H —N(CH₂CH₃)₂ 412.2 2A-12 Cl H

450.2 2A-13 Cl H

464.1 2A-14 Cl H

524.2 2A-15 Cl H

613.2 2A-16 Cl H

539.2 2A-17 Cl H

521.2 2A-18 Cl H

496.1 2A-19 Cl Cl

568.1 2A-20 Cl H

525.2 2A-21 Cl H

481.2 2A-22 Cl H

496.1 2A-23 Cl Cl

555.2 2A-24 Cl H

555.2 2A-25 Cl H

481.1 2A-26 Cl H

516.2 2A-27 Cl H

570.2 2A-28 Cl Cl

488.1 2A-29 Cl H

453.1 2A-30 Cl H

482.1 2A-31 Cl H

570.2 2A-32 Cl Cl

548.2 2A-33 Cl H

451.1 2A-34 Cl H

482.1 2A-35 Cl H

452.2 2A-36 Cl H

530.2 2A-37 Cl Cl

486.1 2A-38 Cl H

492.1 2A-39 Cl H

549.3 2A-40 Cl Cl

512.1 2A-41 Cl H

442.1 2A-42 Cl H

438.1 2A-43 Cl H

452.2 2A-44 Cl H

524.2 2A-45 Cl Cl

517.1 2A-46 Cl H

426.1 2A-47 Cl H

537.2 2A-48 Cl H

507.2 2A-49 Cl H

506.2 2A-50 Cl H

440.1 2A-51 Cl H

484.1 2A-52 Cl H

602.2 2A-53 Cl H

555.2 2A-54 Cl H

440.1 2A-55 Cl H

572.2 2A-56 Cl H

510.2 2A-57 Cl H

438.2 2A-58 Cl H

493.2 2A-59 Cl H

539.2 2A-60 Cl H

517.2 2A-61 Cl H

438.1 2A-62 Cl H

526.2 2A-63 Cl H

492.2 2A-64 Cl Cl

571.1 2A-65 Cl Cl

591.1 2A-66 Cl H

564.0 2A-67 Cl H

550.1 2A-68 Cl H

510.1 2A-69 Cl H

497.0 2A-70 Cl H

480.1 2A-71 Cl Cl —N(CH₂CH₃)₂ 448.2 2A-72 Cl H

454.1 2A-73 Cl Cl

564.0 2A-74 Cl H

536.2 2A-75 Cl H

532.5 2A-76 Cl H

468.2 2A-77 Cl H

482.2 2A-78 Cl H

496.3 2A-79 Cl H

522.3 2A-80 Cl H

538.2 2A-81 Cl H

510.2 2A-82 Cl H

562.2 2A-83 Cl H

494.0 2A-84 Cl H

522.1 2A-85 Cl H

508 2A-86 Cl H

454.3 2A-87 Cl H

454.2 2A-88 Cl H

482.4 2A-89 Cl H

468.3 2A-90 Cl H

440.3 2A-91 Cl H

468.1

Example 3

[0286] Preparation of3-(4-Chlorophenyl)-2-(2-chlorophenyl)-7-piperidinyl-1-yl-2H-pyrazolo[4,3-d]pyrimidine(3A-1):

[0287] To the mixture of piperidine (102 mg, 1.20 mmol), PS-DIEA(polystyrene-diisopropylethylamine; 130 mg, 3.72 mmol/g) in 1.0 mlethanol was added7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidineI-2A-1c (100 mg, 0.26 mmol). The reaction mixture was shaken for 24hours at 50° C. The PS-DIEA was then filtered off, and the filtrate wasconcentrated in vacuo. The residue was purified by chromatography(silica, 20% ethyl acetate in hexanes grading to 50% ethyl acetate inhexanes). The purified product was dissolved in ethyl acetate (1 ml).HCl in ether (0.2 ml of a 1.0 M solution in diethyl ether) was added,and the precipitate that formed was collected by filtration and dried toprovide3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-piperidinyl-1-yl-2H-pyrazolo[4,3-d]pyrimidine3A-1 (94.4 mg): MS: 423.1 (M+1)⁺; ¹H NMR (400 MHz, CD₂Cl₂) δ 8.5 (s,1H), 7.5 (m, 4H), 7.4 (s, 4H), 4.7 (m, 2H), 4.3 (m, 2H), 1.8 (m, 6H).

[0288] The compounds listed in Table 3 below were prepared usingprocedures analogous to those described above for the synthesis ofCompound 3A-1 using the appropriate starting materials which areavailable commercially, prepared using preparations well-known to thoseskilled in the art, or prepared in a manner analogous to routesdescribed above for other intermediates. The compounds listed below weregenerally isolated as their free base and then converted to theircorresponding hydrochloride salts prior to in vivo testing. TABLE 3

Example No. —NRR′ MS(M+H)⁺ 3A-2

452.1 3A-3

490.2 3A-4

452.2 3A-5

496.1 3A-6

440.1 3A-7

454.1 3A-8

452.1 3A-9

410.1 3A-10

444.1 3A-11

474.1 3A-12

454.1 3A-13

426.1 3A-14

497.2 3A-15

529.2 3A-16

490.1 3A-17

472.1 3A-18

486.1 3A-19

460.1 3A-20

527.2 3A-21

481.1 3A-22

490.1 3A-23

466.2 3A-24

474.1 3A-25

474.1 3A-26

472.1 3A-27

488.1 3A-28

483.2 3A-29

433.1 3A-30

447.1 3A-31

463.1 3A-32

516.2 3A-33

488.1 3A-34

447.1 3A-35

461.1 3A-36

447.1 3A-37

469.1 3A-38

486.1 3A-39

414.1 3A-40

438.1 3A-41

410.1 3A-42

525.2 3A-43

440.1 3A-44

481.2 3A-45

556.2 3A-46

454.1 3A-47

438.1 3A-48

482.0 3A-49

496.1 3A-50

466.0 3A-51

425.1 3A-52

438.2 3A-53

546.1

Example 4

[0289] Preparation ofRac-(S,S)-3-(4-Chlorophenyl)-2-(2-chlorophenyl)-7-(2,5-diazabicyclo[2.2.1]hept-2-yl)-2H-pyrazolo[4,3-d]pyrimidine,Hydrochloride Salt (4A-1):

[0290] To the solution of5-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester 2A-46 (595 mg, 1.11 mmol) in dioxane (8 ml) wasadded HCl (2.22 ml, 4 N in dioxane, 8.88 mmol). The reaction mixture wasstirred for 3 hours under nitrogen at room temperature. Then, thereaction mixture was concentrated and co-evaporated with diethyl ether(25 ml). The residue was further dried in a drying pistol under vacuumat 65° C. to giveRac-(S,S)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(2,5-diazabicyclo[2.2.1]hept-2-yl)-2H-pyrazolo[4,3-d]pyrimidineHCl salt 4A-1 (522 mg, 92%): MS: 437.1 (M+1)⁺; ¹H NMR (400 MHz, CD₃OD) δ8.6 (d, J=6.2 Hz, 1H), 7.7 (dd, J=15.8, 7.1 Hz, 1H), 7.6 (m, 2H), 7.5(m, 1H), 7.4 (dd, J=8.3, 3.3 Hz, 2H), 7.3 (t, J=7.5 Hz, 2H), 6.3 (s,0.5H), 5.8 (s, 0.5H), 4.7 (m, 1H), 4.6 (d, J=13.7 Hz, 0.5H), 4.5 (dd,J=13.7, 2.5 Hz, 0.5H), 4.2 (ddd, J=29.5, 14.1, 1.7 Hz, 1H), 3.6 (m, 2H),2.5 (dd, J=24.0, 12.0 Hz, 1H), 2.3 (t, J=11.2 Hz, 1H).

[0291] The compounds listed in Table 4 below were prepared usingprocedures analogous to those described above for the synthesis ofCompound 4A-1 using the appropriate starting materials which areavailable commercially, prepared using preparations well-known to thoseskilled in the art, or prepared in a manner analogous to routesdescribed above for other intermediates. TABLE 4

Example No. —NRR′ MS(M+H)⁺ 4A-2

425.1 4A-3

439.1 4A-4

425.1

Example 5

[0292] Preparation ofRac-(S,S)-3-(4-Chlorophenyl)-2-(2-chlorophenyl)-7-(5-cyclopentyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-2H-pyrazolo[4,3-d]pyrimidine(5A-1):

[0293] To the mixture ofRac-(S,S)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(2,5-diazabicyclo[2.2.1]hept-2-yl)-2H-pyrazolo[4,3-d]pyrimidineHCl salt 4A-1 (50.5 mg, 0.1 mmol), triethylammonium chloride (27 mg, 0.2mmol), and triethylamine (0.028 ml, 0.2 mmol) in absolute ethanol (1 ml)was added cyclopentanone (8.8 ml, 0.1 mmol), followed by borohydrideresin (40 mg, 2.5 mmol/g). The mixture was stirred overnight at roomtemperature. After removal of solvent and resin, the residue was furtherpurified by HPLC to giveRac-(S,S)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(5-cyclopentyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-2H-pyrazolo[4,3-d]pyrimidine5A-1 (23 mg, 46%): MS: 504.8 (M+1)⁺; ¹H NMR (400 MHz, CD₃OD) δ 8.3 (s,1H), 8.2 (s, 1H), 7.6 (m, 4H), 7.4 (m, 3H), 6.1 (s, 0.5H), 5.4 (s,0.5H), 4.6 (m, 1.5H), 4.3 (m, 0.5H), 4.1 (m, 1H), 3.7 (m, 3H), 2.4 (m,2H), 2.3 (m, 1H), 2.2 (m, 1H), 1.8 (m, 2H), 1.6 (m, 4H).

[0294] The compounds listed in Table 5 below were prepared usingprocedures analogous to those described above for the synthesis ofCompound 5A-1 using the appropriate starting materials which areavailable commercially, prepared using preparations well-known to thoseskilled in the art, or prepared in a manner analogous to routesdescribed above for other intermediates. The compounds listed below weregenerally isolated as their free base and then converted to theircorresponding hydrochloride salts prior to in vivo testing. TABLE 5

Example No. —NRR′ MS (M+H)⁺ 5A-2

493.0 5A-3

493.1 5A-4

479.1 5A-5

466.8 5A-6

519.1 5A-7

465.1 5A-8

493.1 5A-9

507.1 5A-1O

481.1

Example 6

[0295] Preparation ofRac-(S,S)-3-(4-Chlorophenyl)-2-(2-chlorophenyl)-7-(5-methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2H-pyrazolo[4,3-d]pyrimidine(6A-1):

[0296] A solution ofRac-(S,S)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(2,5-diazabicyclo[2.2.1]hept-2-yl)-2H-pyrazolo[4,3-d]pyrimidine4A-1 (63 mg, 0.12 mmol) in dichloromethane (2 ml) was charged withtriethylamine (0.1 ml). Methanesulfonyl chloride (0.01 ml, 0.14 mmol)was added via syringe, and the resultant mixture was stirred at 23° C.for 3 days. The reaction mixture was then washed with water (2 ml) andthe layers were separated. The organic solution was dried over anhydrousmagnesium sulfate and concentrated. Purification of the residue byreverse-phase HPLC afforded Rac-(S,S)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(5-methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2H-pyrazolo[4,3-d]pyrimidine6A-1 (63 mg, quantitative): MS: 515.0 (M+1)⁺; ¹H NMR (400 MHz, CD₃OD) δ8.3 (s, 0,5H), 8.1 (s, 0.5H), 7.6 (m, 4H), 7.4 (m, 4H), 6.1 (s, 0.5H),5.2 (s, 0.5H), 4.7 (m, 1H), 4.4 (m, 0.5H), 4.2 (m, 0.5H), 4.0 (m, 1H),3.8 (m, 1H), 3.5 (m, 3H), 3.0 (s, 3H).

[0297] The compounds listed in Table 6 below were prepared usingprocedures analogous to those described above for the synthesis ofCompound 6A-1 using the appropriate starting materials which areavailable commercially, prepared using preparations well-known to thoseskilled in the art, or prepared in a manner analogous to routesdescribed above for other intermediates. The compounds listed below weregenerally isolated as their free base and then converted to theircorresponding hydrochloride salts prior to in vivo testing. TABLE 6

Example No. —NRR′ MS (M+H)⁺ 6A-2

515.0 6A-3

544.2 6A-4

532.2 6A-5

582.9 6A-6

503.2 6A-7

531.2 6A-8

517.2 6A-9

571.1

Example 7

[0298] Preparation of7-(1-Benzylpyrrolidin-3-yloxy)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine(7A-1):

[0299] Sodium hydride (24 mg of a 60% dispersion in mineral oil, 0.6mmol) was added to a solution of 1-benzylpyrrolidin-3-ol (0.1 ml, 0.6mmol) in dimethylformamide (1 ml), and the resultant mixture was stirredat room temperature for 5 min. Next,7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine1-2A-1c (50 mg, 0.13 mmol) was added in one portion, and the mixture wasstirred for 2 hours. The reaction mixture was diluted with methyltert-butyl ether and washed with water (3×). The organic phase was driedover anhydrous magnesium sulfate and concentrated. Purification of theresidue by flash column chromatography (50% ethyl acetate in hexanes)provided the title compound7-(1-benzylpyrrolidin-3-yloxy)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine7A-1 (21 mg): MS: 516.1 (M+1)⁺; ¹H NMR (400 MHz, CDCl₃) δ 8.6 (s, 1H),7.5 (m, 6H), 7.3 (m, 7H), 5.8 (m, 1H), 3.7 (s, 2H), 3.2 (m, 1H), 2.9 (m,1H), 2.8 (m, 1H), 2.7 (m, 1H), 2.5 (m, 1H), 2.2 (m, 1H).

Example 8

[0300] Preparation of3-(4-Chlorophenyl)-2-(2-chlorophenyl)-7-isopropoxy-2H-pyrazolo[4,3-d]pyrimidine(8A-1):

[0301] Sodium (21 mg, 0.9 mmol) was added to 2-propanol (2 ml), and theresultant mixture was stirred at 65° C. for 16 hours. Next,7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidineI-2A-1c (75 mg, 0.2 mmol) was added in one portion, and the mixture wasstirred at 65° C. for 2 hours. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was dried overanhydrous magnesium sulfate and concentrated. Purification of theresidue by flash column chromatography (50% ethyl acetate in hexanes)provided the title compound3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-isopropoxy-2H-pyrazolo[4,3-d]pyrimidine8A-1 (41 mg): MS: 399.1 (M+1)⁺; ¹H NMR (400 MHz, CDCl₃) δ 8.6 (s, 1H),7.6 (d, J=6.6 Hz, 1H), 7.5 (m, 5H), 7.3 (d, J=8.7 Hz, 2H), 5.8(pentuplet, J=6.2 Hz, 1H), 1.5 (d, J=6.2 Hz, 6H).

Example 9

[0302] Preparation of7-(1-Benzhydrylazetidin-3-yloxy)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine(9A-1):

[0303] A solution of7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine(I-2A-1c; 50 mg, 0.13 mmol), 1,4-diazabicyclo[2.2.2]octane (DABCO, 15mg, 0.13 mmol), and triethylamine (0.054 ml, 0.39 mmol) in1,2-dichloroethane (1 ml) was stirred for 16 hours. The reaction mixturewas diluted with dichloromethane and washed with water. The organicswere dried over anhydrous magnesium sulfate and were concentrated.Purification of the residue by flash column chromatography (20% ethylacetate in hexanes) provided the title compound7-(1-benzhydrylazetidin-3-yloxy)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine9A-1 (32 mg): ¹H NMR (400 MHz, CDCl₃) δ 8.6 (s, 1H), 7.4 (complex, 18H),5.6 (m, 1H), 4.5 (br s, 1H), 3.8 (br s, 2H), 3.3 (br s, 2H).

Example 10

[0304] Preparation of3-(4-Chlorophenyl)-2-(2-chlorophenyl)-5-ethyl-6-(2,2,2-trifluoroethyl)-2,6-dihydropyrazolo[4,3-d]pyrimidin-7-one(10A-1):

[0305] A mixture of3-(4-chlorophenyl)-2-(2-chlorophenyl)-5-ethyl-2H-pyrazolo[4,3-d]pyrimidin-7-ol(I-10A-1a; 15 mg, 0.039 mmol), Cs₂CO₃ (52 mg, 0.16 mmol) and CF₃CH₂₁ (39microliters, 0.4 mmol) in dimethylformamide (1 ml) was stirred at 100°C. for 18 hours. The reaction mixture was cooled to room temperature,quenched with saturated aqueous sodium chloride, and extracted withethyl acetate (2×). The combined extracts were washed with saturatedaqueous NaCl, dried over Na₂SO₄, filtered, and concentrated in vacuo.The residue was purified by radial chromatography (1 mm silica gelplate; solvent gradient of 25-50% ethyl acetate/hexane) to provide thedesired product,3-(4-chlorophenyl)-2-(2-chlorophenyl)-5-ethyl-6-(2,2,2-trifluoroethyl)-2,6-dihydropyrazolo[4,3-d]pyrimidin-7-one1A-1 (4 mg): MS (M+1)+467.4; ¹H NMR (400 MHz, CD₂Cl₂) δ 7.59-7.46 (m,6H), 7.37-7.33 (m, 2H), 4.35 (br m, 2H), 3.04 (q, J=7.4 Hz, 2H), 1.40(t, J=7.4 Hz, 3H).

[0306] The compounds listed in Table 7 below were prepared usingprocedures analogous to those described above for the synthesis ofCompound 10A-1 using the appropriate starting materials which areavailable commercially, prepared using preparations well-known to thoseskilled in the art, or prepared in a manner analogous to routesdescribed above for other intermediates. Examples 10A-12, 10A-13 and10A-14 were alkylated at room temperature. TABLE 7

Example No. A —R^(0a) —R^(0b) —R^(1a) —R³ —R⁴ MS (M+1)⁺ 10A-2 N —Cl —H—Cl -i-Pr —OCH₂CF₃ 481.4 10A-3 N —Cl —H —OMe —Me —OCH₂CF₃ 449.4 10A-4 N—Cl —H —Cl —CF₃ —OCH₂CH₃ 453.3 10A-5 N —Cl —H —Cl —CF₃ —OCH₂CF₃ 507.110A-6 N —Cl —H —Cl —Me —OCH₂CF₂CH₂CH₃ 463.4 10A-7 N —Br —H —Cl —Me—OCH₂CF₂CH₃ 492.9 10A-8 N —Br —H —OMe —Me —OCH₂CF₃ 493.0 10A-9 N —Br —H—OMe —Me —OCH₂CF₂CH₃ 489.0 10A-10 N —Cl —H —Br —Me —OCH₂CF₂CH₃ 492.810A-11 N —Cl —H —OMe —Me —OCH₂CF₂CH₃ 445.1 10A-12 N —Cl —H —CF₃ —H—OCH(CH₃)₂ 433.4 10A-13 N —Cl —Me —CF₃ —Me —OCH₂CF₃ 501.5 10A-14 CH —Cl—H —Cl —H —OCH₂CF₃ 438.3

Example 11

[0307] Preparation of2-[3-(4-Chlorophenyl)-7-(2,2-difluoropropoxy)-5-methyl-pyrazolo[4,3-d]pyrimidin-2-yl]-benzonitrile(11A-1):

[0308] A mixture of2-(2-bromophenyl)-3-(4-chlorophenyl)-7-(2,2-difluoropropoxy)-5-methyl-2H-pyrazolo[4,3-d]pyrimidine(10A-7, 50 mg, 0.1 mmol), Zn(CN)₂ (20 mg, 0.17 mmol), Pd(PPh₃)₄ (15 mg,0.01 mmol) in DMF (1 ml) was heated in a microwave apparatus (EmrysOptimizer, Personal Chemistry) at 200° C. for 3 minutes. The reactionmixture was quenched with saturated aqueous NaCl and extracted withethyl acetate (2×). The combined organic extracts were dried andconcentrated under vacuum. The crude residue was purified via HPLC(Shimadzu) using a solvent gradient of 30% CH₃CN/hexanes to 100% CH₃CNto give the desired product,2-[3-(4-chlorophenyl)-7-(2,2-difluoropropoxy)-5-methylpyrazolo[4,3-d]pyrimidin-2-yl]-benzonitrile(11A-1), as a colorless solid (25 mg): MS (M+1)+440.0; ¹H NMR (400 MHz,CDCl₃) δ 7.80-7.64 (m, 4H), 7.40-7.26 (m, 4H), 4.8 (t, J=11.6 Hz, 2H),2.7 (s, 3H), 1.79 (t, J=18.67 Hz, 3H).

Example 12

[0309] Preparation of3-(4-Chlorophenyl)-2-(2-chlorophenyl)-7-ethoxy-2H-pyrazolo[4,3-d]pyrimidine(12A-1):

[0310] To a solution of7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine(I-2A-1c; 50 mg, 0.133 mmol) and ethanol (0.016 ml, 0.27 mmol) intetrahydrofuran (1.5 ml) was added NaH (60% dispersion in oil, 14 mg,0.33 mmol). After stirring for 1 hour, the reaction was extracted fromsaturated aqueous NaHCO₃ with ethyl acetate, the combined organic layerswere dried (MgSO₄), concentrated and purified on a Biotage® Flash 12Mcolumn using a solvent gradient of 0-20% ethyl acetate in hexanes aseluant to afford 12A-1 (46 mg, 92%) as a colorless solid: +ESI MS (M+1)385.4; ¹H NMR (400 MHz, CD₂Cl₂) δ 8.56 (s, 1H), 7.58-7.46 (m, 6H), 7.34(d, J=8.7 Hz, 2H), 4.70 (q, J=7.1 Hz, 2H), 1.53 (t, J=7.1 Hz, 3H).

[0311] The compounds listed in Table 8 below were prepared usingprocedures analogous to those described above for the synthesis ofCompound 12A-1 using the appropriate starting materials which areavailable commercially, prepared using preparations well-known to thoseskilled in the art, or prepared in a manner analogous to routesdescribed above for other intermediates. TABLE 8

Example No. A —R⁴ MS (M+H)⁺ 12A-2 N —OCH₂CH₂CH₃ 399.4 12A-3 N—OCH₂CH₂CH₂CH₃ 413.4 12A-4 CH —OCH(CH₃)₂ 398.4

Pharmacological Testing

[0312] The utility of the compounds of the present invention in thepractice of the instant invention can be evidenced by activity in atleast one of the protocols described hereinbelow. The following acronymsare used in the protocols described below.

[0313] BSA—bovine serum albumin

[0314] DMSO—dimethylsulfoxide

[0315] EDTA—ethylenediamine tetracetic acid

[0316] PBS—phosphate-buffered saline

[0317] EGTA—ethylene glycol-bis(P-aminoethyl ether)N,N,N′,N′-tetraacetic acid

[0318] GDP—guanosine diphosphate

[0319] sc—subcutaneous

[0320] po—orally

[0321] ip—intraperitoneal

[0322] icv—intra cerebro ventricular

[0323] iv—intravenous

[0324] [³H]SR141716A-radiolabeledN-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride available from Amersham Biosciences, Piscataway, N.J.

[0325] [³H]CP-55940-radiolabled5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)-cyclohexyl]-phenolavailable from NEN Life Science Products, Boston, Mass.

[0326]AM251-N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-pyrazole-3-carboxamideavailable from Tocris™, Ellisville, Mo.

[0327] All of the compounds listed in the Example section above weretested in the CB-1 receptor binding assay below. The compounds provideda range of binding activities from 0.2 nM to 1.6 μM. The compoundshaving an activity <20 nM were then tested in the CB-1 GTPγ [³⁵S]Binding Assay and the CB-2 binding assay described below in theBiological Binding Assays section. Selected compounds were then testedin vivo using one or more of the functional assays described in theBiological Functional Assays section below.

In Vitro Biological Assays

[0328] Bioassay systems for determining the CB-1 and CB-2 receptorbinding properties and pharmacological activity of cannabinoid receptorligands are described by Roger G. Pertwee in “Pharmacology ofCannabinoid Receptor Ligands” Current Medicinal Chemistry, 6, 635-664(1999) and in WO 92/02640 (U.S. application Ser. No. 07/564,075 filedAug. 8, 1990, incorporated herein by reference).

[0329] The following assays were designed to detect compounds thatinhibit the binding of [³H]-SR141716A (selective radiolabeled CB-1receptor ligand) and[³H]-5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)-cyclohexyl]-phenol;radiolabeled CB-1/CB-2 receptor ligand) to their respective receptors.

Rat CB-1 Receptor Binding Protocol

[0330] PelFreeze brains (available from Pel Freeze Biologicals, Rogers,Ark.) were cut up and placed in tissue preparation buffer (5 mM TrisHCl, pH=7.4 and 2 mM EDTA), polytroned at high speed and kept on ice for15 minutes. The homogenate was then spun at 1,000×g for 5 minutes at 4°C. The supernatant was recovered and centrifuged at 100,000 X G for 1hour at 4° C. The pellet was then re-suspended in 25 ml of TME (25 nMTris, pH=7.4, 5 mM MgCl₂, and 1 mM EDTA) per brain used. A protein assaywas performed and 200 μl of tissue totaling 20 μg was added to theassay.

[0331] The test compounds were diluted in drug buffer (0.5% BSA, 10%DMSO and TME) and then 25 μl were added to a deep well polypropyleneplate. [³H]-SR141716A was diluted in a ligand buffer (0.5% BSA plus TME)and 25 μl were added to the plate. A BCA protein assay was used todetermine the appropriate tissue concentration and then 200 μl of ratbrain tissue at the appropriate concentration was added to the plate.The plates were covered and placed in an incubator at 20° C. for 60minutes. At the end of the incubation period 250 μl of stop buffer (5%BSA plus TME) was added to the reaction plate. The plates were thenharvested by Skatron onto GF/B filtermats presoaked in BSA (5 mg/ml)plus TME. Each filter was washed twice. The filters were driedovernight. In the morning the filters were counted on a WallacBetaplate™ counter (available from PerkinElmer Life Sciences™, Boston,Mass.).

Human CB-1 Receptor Binding Protocol

[0332] Human embryonic kidney 293 (HEK 293) cells transfected with theCB-1 receptor cDNA (obtained from Dr. Debra Kendall, University ofConnecticut) were harvested in homogenization buffer (10 mM EDTA, 10 mMEGTA, 10 mM Na Bicarbonate, protease inhibitors; pH=7.4), andhomogenized with a Dounce Homogenizer. The homogenate was then spun at1,000×G for 5 minutes at 4° C. The supernatant was recovered andcentrifuged at 25,000×G for 20 minutes at 4° C. The pellet was thenre-suspended in 10 ml of homogenization buffer and re-spun at 25,000×Gfor 20 minutes at 4° C. The final pellet was re-suspended in 1 ml of TME(25 mM Tris buffer (pH=7.4) containing 5 mM MgCl₂ and 1 mM EDTA). Aprotein assay was performed and 200 ii of tissue totaling 20 μg wasadded to the assay.

[0333] The test compounds were diluted in drug buffer (0.5% BSA, 10%DMSO and TME) and then 25 jI were added to a deep well polypropyleneplate. [³H]—SR141716A was diluted in a ligand buffer (0.5% BSA plus TME)and 25 μl were added to the plate. The plates were covered and placed inan incubator at 30° C. for 60 minutes. At the end of the incubationperiod 250 μl of stop buffer (5% BSA plus TME) was added to the reactionplate. The plates were then harvested by Skatron onto GF/B filtermatspresoaked in BSA (5 mg/ml) plus TME. Each filter was washed twice. Thefilters were dried overnight. In the morning, the filters were countedon a Wallac Betaplate™ counter (available from PerkinElmer LifeSciences™, Boston, Mass.).

CB-2 Receptor Binding Protocol

[0334] Chinese hamster ovary-K1 (CHO-K1) cells transfected with CB-2receptor cDNA (obtained from Dr. Debra Kendall, University ofConnecticut) were harvested in tissue preparation buffer (5 mM Tris-HClbuffer (pH=7.4) containing 2 mM EDTA), polytroned at high speed and kepton ice for 15 minutes. The homogenate was then spun at 1,000×G for 5minutes at 4° C. The supernatant was recovered and centrifuged at100,000×G for 1 hour at 4° C. The pellet was then re-suspended in 25 mlof TME (25 mM Tris buffer (pH=7.4) containing 5 mM MgCl₂ and 1 mM EDTA)per brain used. A protein assay was performed and 200 μl of tissuetotaling 10 μg was added to the assay.

[0335] The test compounds were diluted in drug buffer (0.5% BSA, 10%DMSO, and 80.5% TME) and then 25 μl were added to the deep wellpolypropylene plate.[³H]-5-(1,1-Dimethyl-heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenolwas diluted a ligand buffer (0.5% BSA and 99.5% TME) and then 25 μl wereadded to each well at a concentration of 1 nM. A BCA protein assay wasused to determine the appropriate tissue concentration and 200 μl of thetissue at the appropriate concentration was added to the plate. Theplates were covered and placed in an incubator at 30° C. for 60 minutes.At the end of the incubation period 250 μl of stop buffer (5% BSA plusTME) was added to the reaction plate. The plates were then harvested bySkatron format onto GF/B filtermats presoaked in BSA (5 mg/ml) plus TME.Each filter was washed twice. The filters were dried overnight. Thefilters were then counted on the Wallac Betaplate™ counter.

CB-1 Receptor GTPγ [³⁵S] Binding Assay

[0336] Membranes were prepared from CHO-K1 cells stably transfected withthe human CB-1 receptor cDNA. Membranes were prepared from cells asdescribed by Bass et al., in “Identification and characterization ofnovel somatostatin antagonists,” Molecular Pharmacology, 50, 709-715(1996). GTPγ[³⁵S] binding assays were performed in a 96 well FlashPlate™format in duplicate using 100 μM GTPγ[³⁵S] and 10 μg membrane per wellin assay buffer composed of 50 mM Tris HCl, pH 7.4, 3 mM MgCl₂, pH 7.4,10 mM MgCl₂, 20 mM EGTA, 100 mM NaCl, 30 μM GDP, 0.1% bovine serumalbumin and the following protease inhibitors: 100 μg/ml bacitracin, 100μg/ml benzamidine, 5 μg/ml aprotinin, 5 μg/ml leupeptin. The assay mixwas then incubated with increasing concentrations of antagonist (10⁻¹⁰ Mto 10⁻⁵ M) for 10 minutes and challenged with the cannabinoid agonist5-(1,1-dimethyl-heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenol(10 μM). Assays were performed at 30° C. for one hour. The FlashPlates™were then centrifuged at 2000×G for 10 minutes. Stimulation of GTPγ[³⁵S]binding was then quantified using a Wallac Microbeta.EC₅₀ calculationsdone using Prism™ by Graphpad.

[0337] Inverse agonism was measured in the absense of agonist.

CB-1 Receptor FLIPR-based Functional Assay Protocol

[0338] CHO-K1 cells co-transfected with the human CB-1 receptor cDNA(obtained from Dr. Debra Kendall, University of Connecticut) and thepromiscuous G-protein G16 were used for this assay. Cells were plated 48hours in advance at 12500 cells per well on collagen coated 384 wellblack clear assay plates. Cells were incubated for one hour with 4 μMFluo-4 μM (Molecular Probes) in DMEM (Gibco) containing 2.5 mMprobenicid and pluronic acid (0.04%). The plates were then washed 3times with HEPES-buffered saline (containing probenicid; 2.5 mM) toremove excess dye. After 20 min the plates were added to the FLIPRindividually and fluorescence levels was continuously monitored over an80 second period. Compound additions were made simultaneously to all 384wells after 20 seconds of baseline. Assays were performed in triplicateand 6 point concentration-response curves generated. Antagonistcompounds were subsequently challenged with 3 μM WIN 55,212-2 (agonist).Data were analyzed using Graph Pad Prism.

Detection of Inverse Agonists

[0339] The following cyclic-AMP assay protocol using intact cells wasused to determine inverse agonist activity.

[0340] Cells were plated into a 96-well plate at a plating density of10,000-14,000 cells per well at a concentration of 100 μl per well. Theplates were incubated for 24 hours in a 37° C. incubator. The media wasremoved and media lacking serum (100 μl) was added. The plates were thenincubated for 18 hours at 37° C.

[0341] Serum free medium containing 1 mM IBMX was added to each wellfollowed by 10 μl of test compound (1:10 stock solution (25 mM compoundin DMSO) into 50% DMSO/PBS) diluted 10× in PBS with 0.1% BSA. Afterincubating for 20 minutes at 37° C., 2 μM of forskolin was added andthen incubated for an additional 20 minutes at 37° C. The media wasremoved, 100 μl of 0.01 N HCl was added and then incubated for 20minutes at room temperature. Cell lysate (75 μl) along with 25 μl ofassay buffer (supplied in FlashPlate™ cAMP assay kit available from NENLife Science Products Boston, Mass.) into a Flashplate. cAMP standardsand cAMP tracer were added following the kit's protocol. The flashplatewas then incubated for 18 hours at 4° C. The content of the wells wereaspirated and counted in a Scintillation counter.

In Vivo Biological Assays

[0342] Cannabinoid agonists such as Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and5-(1,1-dimethyl-heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenolhave been shown to affect four characteristic behaviors in mice,collectively known as the Tetrad. For a description of these behaviorssee: Smith, P. B., et al. in “The pharmacological activity ofanandamide, a putative endogenous cannabinoid, in mice.” J. Pharmacol.Exp. Ther., 270(1), 219-227 (1994) and Wiley, J., et al. in“Discriminative stimulus effects of anandamide in rats,” Eur. J.Pharmacol., 276(1-2), 49-54 (1995). Reversal of these activities in thelocomotor activity, catalepsy, hypothermia, and hot plate assaysdescribed below provides a screen for in vivo activity of CB-1 receptorantagonists.

[0343] All data is presented as % reversal from agonist alone using thefollowing formula:(5-(1,1-dimethyl-heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenol/agonist-vehicle/agonist)/(vehicle/vehicle-vehicle/agonist).Negative numbers indicate a potentiation of the agonist activity ornon-antagonist activity. Positive numbers indicate a reversal ofactivity for that particular test.

Locomotor Activity

[0344] Male ICR mice (n=6; 17-19 g, Charles River Laboratories, Inc.,Wilmington, Mass.) were pre-treated with test compound (sc, po, ip, oricv). Fifteen minutes later, the mice were challenged with5-(1,1-dimethyl-heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenol(sc). Twenty-five minutes after the agonist injection, the mice wereplaced in clear acrylic cages (431.8 cm×20.9 cm×20.3 cm) containingclean wood shavings. The subjects were allowed to explore surroundingsfor a total of about 5 minutes and the activity was recorded by infraredmotion detectors (available from Coulbourn Instruments™, Allentown, Pa.)that were placed on top of the cages. The data was computer collectedand expressed as “movement units.”

Catalepsy

[0345] Male ICR mice (n=6; 17-19 g upon arrival) were pre-treated withtest compound (sc, po, ip or icv). Fifteen minutes later, the mice werechallenged with5-(1,1-dimethyl-heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenol(sc). Ninety minutes post injection, the mice were placed on a 6.5 cmsteel ring attached to a ring stand at a height of about 12 inches. Thering was mounted in a horizontal orientation and the mouse was suspendedin the gap of the ring with fore- and hind-paws gripping the perimeter.The duration that the mouse remained completely motionless (except forrespiratory movements) was recorded over a 3-minute period.

[0346] The data were presented as a percent immobility rating. Therating was calculated by dividing the number of seconds the mouseremains motionless by the total time of the observation period andmultiplying the result by 100. A percent reversal from the agonist wasthen calculated.

Hypothermia

[0347] Male ICR mice (n=5; 17-19 g upon arrival) were pretreated withtest compounds (sc, po, ip or icv). Fifteen minutes later, mice werechallenged with the cannabinoid agonist5-(1,1-dimethyl-heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenol(sc). Sixty-five minutes post agonist injection, rectal bodytemperatures were taken. This was done by inserting a small thermostatprobe approximately 2-2.5 cm into the rectum. Temperatures were recordedto the nearest tenth of a degree

Hot Plate

[0348] Male ICR mice (n=7; 17-19 g upon arrival) are pre-treated withtest compounds (sc, po, ip or iv). Fifteen minutes later, mice werechallenged with a cannabinoid agonist5-(1,1-dimethyl-heptyl)-2-[5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenol(sc). Forty-five minutes later, each mouse was tested for reversal ofanalgesia using a standard hot plate meter (Columbus Instruments). Thehot plate was 10″×10″×0.75″ with a surrounding clear acrylic wall.Latency to kick, lick or flick hindpaw or jump from the platform wasrecorded to the nearest tenth of a second. The timer was experimenteractivated and each test had a 40 second cut off. Data were presented asa percent reversal of the agonist induced analgesia.

Food Intake

[0349] The following screen was used to evaluate the efficacy of testcompounds for inhibiting food intake in Sprague-Dawley rats after anovernight fast.

[0350] Male Sprague-Dawley rats were obtained from Charles RiverLaboratories, Inc. (Wilmington, Mass.). The rats were individuallyhoused and fed powdered chow They were maintained on a 12-hourlight/dark cycle and received food and water ad libitum. The animalswere acclimated to the vivarium for a period of one week before testingwas conducted. Testing was completed during the light portion of thecycle.

[0351] To conduct the food intake efficacy screen, rats were transferredto individual test cages without food the afternoon prior to testing,and the rats were fasted overnight. After the overnight fast, rats weredosed the following morning with vehicle or test compounds. A knownantagonist was dosed (3 mg/kg) as a positive control, and a controlgroup received vehicle alone (no compound). The test compounds weredosed at ranges between 0.1 and 100 mg/kg depending upon the compound.The standard vehicle was 0.5% (w/v) methylcellulose in water and thestandard route of administration was oral. However, different vehiclesand routes of administration were used to accommodate various compoundswhen required. Food was provided to the rats 30 minutes after dosing andthe Oxymax automated food intake system (Columbus Instruments, Columbus,Ohio) was started. Individual rat food intake was recorded continuouslyat 10-minute intervals for a period of two hours. When required, foodintake was recorded manually using an electronic scale; food was weighedevery 30 minutes after food was provided up to four hours after food wasprovided. Compound efficacy was determined by comparing the food intakepattern of compound-treated rats to vehicle and the standard positivecontrol.

Alcohol Intake

[0352] The following protocol evaluates the effects of alcohol intake inalcohol preferring (P) female rats (bred at Indiana University) with anextensive drinking history. The following references provide detaileddescriptions of P rats: Li, T.-K., et al., “Indiana selection studies onalcohol related behaviors” in Development of Animal Models asPharmacogenetic Tools (eds McClearn C. E., Deitrich R. A. and Erwin V.G.), Research Monograph 6, 171-192 (1981) NIAAA, ADAMHA, Rockville, Md.;Lumeng, L, et al., “New strains of rats with alcohol preference andnonpreference” Alcohol And Aldehyde Metabolizing Systems, 3, AcademicPress, New York, 537-544 (1977); and Lumeng, L, et al., “Differentsensitivities to ethanol in alcohol-preferring and -nonpreferring rats,”Pharmacol, Biochem Behav., 16, 125-130 (1982).

[0353] Female rats were given 2 hours of access to alcohol (10% v/v andwater, 2-bottle choice) daily at the onset of the dark cycle. The ratswere maintained on a reverse cycle to facilitate experimenterinteractions. The animals were initially assigned to four groups equatedfor alcohol intakes: Group 1—vehicle (n=8); Group 2—positive control(e.g. 5.6 mg/kg AM251; n=8); Group 3—low dose test compound (n=8); andGroup 4—high dose of test compound (n=8). Test compounds were generallymixed into a vehicle of 30% (w/v) β-cyclodextrin in distilled water at avolume of 1-2 ml/kg. Vehicle injections were given to all groups for thefirst two days of the experiment. This was followed by 2 days of druginjections (to the appropriate groups) and a final day of vehicleinjections. On the drug injection days, drugs were given sc 30 minutesprior to a 2-hour alcohol access period. Alcohol intake for all animalswas measured during the test period and a comparison was made betweendrug and vehicle-treated animals to determine effects of the compoundson alcohol drinking behavior.

[0354] Additional drinking studies were done utilizing female C57Bl/6mice (Charles River). Several studies have shown that this strain ofmice will readily consume alcohol with little to no manipulationrequired (Middaugh et al., “Ethanol Consumption by C57BL/6 Mice:Influence of Gender and Procedural Variables” Alcohol, 17 (3),175-183,1999; Le et al., “Alcohol Consumption by C57BL/6, BALA/c, andDBA/2 Mice in a Limited Access Paradigm” Pharmacology Biochemistry andBehavior, 47, 375-378, 1994).

[0355] For our purposes, upon arrival (17-19 g) mice were individuallyhoused and given unlimited access to powdered rat chow, water and a 10%(w/v) alcohol solution. After 2-3 weeks of unlimited access, water wasrestricted for 20 hours and alcohol was restricted to only 2 hoursaccess daily. This was done in a manner that the access period was thelast 2 hours of the dark part of the light cycle.

[0356] Once drinking behavior stabilized, testing commenced. Mice wereconsidered stable when the average alcohol consumption for 3 days was+20% of the average for all 3 days. Day 1 of test consisted of all micereceiving vehicle injection (sc or ip). Thirty to 120 minutes postinjection access was given to alcohol and water. Alcohol consumption forthat day was calculated (g/kg) and groups were assigned (n=7-10) so thatall groups had equivocal alcohol intake. On day 2 and 3, mice wereinjected with vehicle or drug and the same protocol as the previous daywas followed. Day 4 was wash out and no injections were given. Data wasanalyzed using repeated measures ANOVA. Change in water or alcoholconsumption was compared back to vehicle for each day of the test.Positive results would be interpreted as a compound that was able tosignificantly reduce alcohol consumption while having no effect on water

Oxygen Consumption

[0357] Methods:

[0358] Whole body oxygen consumption was measured using an indirectcalorimeter (Oxymax from Columbus Instruments, Columbus, Ohio) in maleSprague Dawley rats (if another rat strain or female rats are used, itwill be specified). Rats (300-380 g body weight) were placed in thecalorimeter chambers and the chambers were placed in activity monitors.These studies were done during the light cycle. Prior to the measurementof oxygen consumption, the rats were fed standard chow ad libitum.During the measurement of oxygen consumption, food was not available.Basal pre-dose oxygen consumption and ambulatory activity were measuredevery 10 minutes for 2.5 to 3 hours. At the end of the basal pre-dosingperiod, the chambers were opened and the animals were administered asingle dose of compound (the usual dose range is 0.001 to 10 mg/kg) byoral gavage (or other route of administration as specified, i.e., sc,ip, iv). Drugs were prepared in methylcellulose, water or otherspecified vehicle (examples include PEG400, 30% beta-cyclo dextran andpropylene glycol). Oxygen consumption and ambulatory activity weremeasured every 10 minutes for an additional 1-6 hours post-dosing.

[0359] The Oxymax calorimeter software calculated the oxygen consumption(ml/kg/h) based on the flow rate of air through the chambers anddifference in oxygen content at inlet and output ports. The activitymonitors have 15 infrared light beams spaced one inch apart on eachaxis, ambulatory activity was recorded when two consecutive beams arebroken and the results are recorded as counts.

[0360] Resting oxygen consumption, during pre- and post-dosing, wascalculated by averaging the 10-minute O₂ consumption values, excludingperiods of high ambulatory activity (ambulatory activity count>100) andexcluding the first 5 values of the pre-dose period and the first valuefrom the post-dose period. Change in oxygen consumption was reported aspercent and was calculated by dividing the post-dosing resting oxygenconsumption by the pre-dose oxygen consumption *100. Experiments wouldtypically be done with n=4-6 rats and results reported are mean +/−SEM.

[0361] Interpretation:

[0362] An increase in oxygen consumption of >10% was considered apositive result. Historically, vehicle-treated rats have no change inoxygen consumption from pre-dose basal.

What is claimed is:
 1. A compound of Formula (I)

wherein A is N or C(R²), where R² is hydrogen, (C₁-C₄)alkyl,halo-substituted (C₁-C₄)alkyl, or (C₁-C₄)alkoxy; R⁰ is an optionallysubstituted aryl or an optionally substituted heteroaryl; R¹ is anoptionally substituted aryl or an optionally substituted heteroaryl; R³is hydrogen, (C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl, or(C₁-C₄)alkoxy; R⁴ is (i) a group having Formula (IA) or Formula (IB)

 where R^(4a) is hydrogen or (C₁-C₃)alkyl; R^(4b) and R^(4b′) are eachindependently hydrogen, cyano, hydroxy, amino, H₂NC(O)—, or a chemicalmoiety selected from the group consisting of (C₁-C₆)alkyl,(C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a partiallyor fully saturated carbocyclic ring, where said moiety is optionallysubstituted with one or more substituents, or either R^(4b) or R^(4b′)taken together with R^(4e), R^(4e′), R^(4f), or R^(4f′) forms a bond, amethylene bridge, or an ethylene bridge; X is a bond, —CH₂CH₂— or—C(R^(4c))(R^(4c′))—, where R^(4c) and R^(4c′) are each independentlyhydrogen, cyano, hydroxy, amino, H₂NC(O)—, or a chemical moiety selectedfrom the group consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, ((C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a 3-6 membered partially or fully saturated heterocycle, anda 3-6 membered partially or fully saturated carbocyclic ring, where saidmoiety is optionally substituted with one or more substituents, oreither R^(4c) or R^(4c′) taken together with R^(4e), R^(4e′), R^(4f), orR^(4f′) forms a bond, a methylene bridge or an ethylene bridge; Y isoxygen, sulfur, —C(O)—, or —C(R^(4d))(R^(4d′))—, where R^(4d) andR^(4d′) are each independently hydrogen, cyano, hydroxy, amino,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, ((C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a 3-6membered partially or fully saturated carbocyclic ring, where saidmoiety is optionally substituted with one or more substituents, orR^(4d) and R^(4d′) taken together form a 3-6 membered partially or fullysaturated carbocyclic ring, 3-6 membered partially or fully saturatedheterocyclic ring, a 5-6 membered lactone ring, or a 4-6 membered lactamring, where said carbocyclic ring, said heterocyclic ring, said lactonering and said lactam ring are optionally substituted with one or moresubstituents and said lactone ring and said lactam ring optionallycontain an additional heteroatom selected from oxygen, nitrogen orsulfur, or Y is —NR^(4d″)—, where R^(4d″) is a hydrogen or a chemicalmoiety selected from the group consisting of (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₁-C₃)alkylsulfonyl-, (C₁-C₃)alkylaminosulfonyl-,di(C₁-C₃)alkylaminosulfonyl-, acyl, (C₁-C₆)alkyl-O—C(O)—, aryl, andheteroaryl, where said moiety is optionally substituted with one or moresubstituents; Z is a bond, —CH₂CH₂—, or —C(R^(4e))(R^(4e′))—, whereR^(4e) and R^(4e′) are each independently hydrogen, cyano, hydroxy,amino, H₂NC(O)—, or a chemical moiety selected from the group consistingof (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, ((C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a 3-6membered partially or fully saturated carbocyclic ring, where saidmoiety is optionally substituted with one or more substituents, oreither R^(4e) or R⁴′ taken together with R^(4b), R^(4b′), R^(4c), orR^(4c′) forms a bond, a methylene bridge or an ethylene bridge; andR^(4f) and R^(4f′) are each independently hydrogen, cyano, hydroxy,amino, H₂NC(O)—, or a chemical moiety selected from the group consistingof (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, ((C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a 3-6membered partially or fully saturated carbocyclic ring, where saidmoiety is optionally substituted with one or more substituents, oreither R^(4f) or R^(4f′) taken together with R^(4b), R^(4b′), R^(4c), orR^(4c′) forms a bond, a methylene bridge or an ethylene bridge; (ii) agroup having Formula (IC)

where R⁵ and R⁶ are each independently hydrogen, aryl, or (C₁-C₄)alkyl,and R⁷ is an optionally substituted (C₁-C₄)alkyl-, or an optionallysubstituted 4-6 membered partially or fully saturated heterocylic ringcontaining 1 to 2 heteroatoms independently selected from oxygen, sulfuror nitrogen, or R⁵ and R⁵ or R⁵ and R⁷ taken together form a 5-6membered lactone, 4-6 membered lactam, or a 4-6 membered partially orfully saturated heterocycle containing 1 to 2 heteroatoms independentlyselected from oxygen, sulfur or nitrogen, where said lactone, saidlactam and said heterocycle are optionally substituted with one or moresubstituents; (iii) an amino group having attached thereto at least onechemical moiety selected from the group consisting of (C₁-C₈)alkyl,aryl, aryl(C₁-C₄)alkyl, a 3-8 membered partially or fully saturatedcarbocyclic ring, hydroxy(C₁-C₆)alkyl, (C₁-C₃)alkoxy(C₁-C₆)alkyl,heteroaryl(C₁-C₃)alkyl, and a fully or partially saturated heterocycle,where said chemical moiety is optionally substituted with one or moresubstituents; or (iv) an (C₁-C₆)alkyl group having attached thereto atleast one chemical moiety selected from the group consisting of hydroxy,(C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino, di((C₁-C₆)alkyl)amino(C₁-C₃)alkylsulfonyl, (C₁-C₃)alkylsulfamyl, di((C₁-C₃)alkyl)sulfamyl,acyloxy, a fully or partially saturated heterocycle, and a fully orpartially saturated carbocyclic ring, where said chemical moiety isoptionally substituted with one or more substituents; a pharmaceuticallyacceptable salt thereof, a prodrug of said compound or said salt, or asolvate or hydrate of said compound, said salt or said prodrug.
 2. Thecompound of claim 1 wherein R⁴ is a group having Formula (IA)

where, R^(4b) and R^(4b′) are each independently hydrogen, H₂NC(O)—, ora chemical moiety selected from the group consisting of (C₁-C₆)alkyl,acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6 membered partially orfully saturated heterocycle, and a partially or fully saturatedcarbocyclic ring, where said moiety is optionally substituted with oneor more substituents, or R^(4b) or R^(4b′) taken together with R^(4e),R^(4e′), R^(4f), or R^(4f′) forms a bond, a methylene bridge, or anethylene bridge; X is a bond, —CH₂CH₂— or —C(R^(4c))(R^(4c′))—, whereR^(4c) is hydrogen, cyano, hydroxy, amino, H₂NC(O)—, or a chemicalmoiety selected from the group consisting of (C₁-C₆)alkyl,(C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a partiallyor fully saturated carbocyclic ring, where said moiety is optionallysubstituted with one or more substituents, or R^(4c) taken together withR^(4e), R^(4e′), R^(4f), or R^(4f′) forms a bond, a methylene bridge, oran ethylene bridge, and R^(4c′) is hydrogen, H₂NC(O)—, or a chemicalmoiety selected from the group consisting of (C₁-C₆)alkyl, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,aryl, heteroaryl, a 3-6 membered partially or fully saturatedheterocycle, and a partially or fully saturated carbocyclic ring, wheresaid moiety is optionally substituted with one or more substituents, orR^(4c′) taken together with R^(4e), R^(4e′), R^(4f), or R^(4f′) forms abond, a methylene bridge, or an ethylene bridge; Y is oxygen, sulfur,—C(O)—, or —C(R^(4d))(R^(4d′))—, where R^(4d) is hydrogen, cyano,hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a 3-6 membered partially or fully saturated heterocycle, anda partially or fully saturated carbocyclic ring, where said moiety isoptionally substituted with one or more substituents, and R^(4d′) ishydrogen, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6membered partially or fully saturated heterocycle, and a partially orfully saturated carbocyclic ring, where said moiety is optionallysubstituted with one or more substituents, or R^(4d) and R^(4d′) takentogether form a 3-6 membered partially or fully saturated carbocyclicring, a 3-6 membered partially or fully saturated heterocyclic ring, a5-6 membered lactone ring, or a 4-6 membered lactam ring, where saidcarbocyclic ring, said heterocyclic ring, said lactone ring and saidlactam ring are optionally substituted with one or more substituents andsaid lactone ring and said lactam ring optionally contain an additionalheteroatom selected from oxygen, nitrogen or sulfur, or Y is —NR^(4d″)—,where R^(4d″) is a hydrogen or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₃)alkylsulfonyl-,(C₁-C₃)alkylaminosulfonyl-, di(C₁-C₃)alkylaminosulfonyl-, acyl.(C₁-C₆)alkyl-O—C(O)—, aryl, and heteroaryl, where said moiety isoptionally substituted with one or more substituents; Z is a bond,—CH₂CH₂—, or —C(R^(4e))(R^(4e′))—, where R^(4e) is hydrogen, cyano,hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a 3-6 membered partially or fully saturated heterocycle, anda partially or fully saturated carbocyclic ring, where said moiety isoptionally substituted with one or more substituents, or R^(4e) takentogether with R^(4b), R^(4b′), R^(4c), or R^(4c′) forms a bond, amethylene bridge, or an ethylene bridge, and R^(4e′) is hydrogen,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6 membered partially orfully saturated heterocycle, and a partially or fully saturatedcarbocyclic ring, where said moiety is optionally substituted with oneor more substituents, or R^(4e′) taken together with R^(4b), R^(4b′),R^(4c), or R^(4c′) forms a bond, a methylene bridge, or an ethylenebridge; and R^(4f) and R^(4f′) are each independently hydrogen,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6 membered partially orfully saturated heterocycle, and a partially or fully saturatedcarbocyclic ring, where said moiety is optionally substituted with oneor more substituents, or R^(4f) or R^(4f′) taken together withR^(4b)R^(4b′), R^(4c), or R^(4c′) forms a bond, a methylene bridge, oran ethylene bridge; a pharmaceutically acceptable salt thereof, or asolvate or hydrate of said compound or said salt.
 3. The compound ofclaim of 2 wherein R⁰ and R¹ are each independently a substitutedphenyl; R^(4b) is hydrogen, an optionally substituted (C₁-C₃)alkyl, ortaken together with R^(4e), R^(4e′), R^(4f), or R^(4f′) forms a bond, amethylene bridge, or an ethylene bridge; R^(4b′) is hydrogen, anoptionally substituted (C₁-C₃)alkyl, or taken together with R^(4e),R^(4e′), R^(4f), or R^(4f′) forms a bond, a methylene bridge, or anethylene bridge; R^(4f) is hydrogen, an optionally substituted(C₁-C₃)alkyl, or taken together with R^(4b), R^(4b′), R^(4c), or R^(4c′)forms a bond, a methylene bridge, or an ethylene bridge; and R^(4f) ishydrogen, an optionally substituted (C₁-C₃)alkyl, or taken together withR^(4b), R^(4b′), R^(4c), or R^(4c′) forms a bond, a methylene bridge, oran ethylene bridge; a pharmaceutically acceptable salt thereof, or asolvate or hydrate of said compound or said salt.
 4. The compound ofclaim 3 wherein X is —C(R^(4c))(R^(4c′))—, where R^(4c) and R^(4c′) areeach independently hydrogen, H₂NC(O)—, or a chemical moiety selectedfrom (C₁-C₆)alkyl, (C₁-C₄)alkyl-NH—C(O)—, or ((C₁-C₄)alkyl)₂N—C(O)—,where said moiety is optionally substituted with one or moresubstituents, or either R^(4c) or R^(4c′) taken together with R^(4e),R^(4e′), R^(4f), or R^(4f′) forms a bond, a methylene bridge or anethylene bridge; Y is —NR^(4d″)—, where R^(4d″) is a hydrogen or achemical moiety selected from the group consisting of (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₁-C₃)alkylsulfonyl, (C₁-C₃)alkylaminosulfonyl,di(C₁-C₃)alkylaminosulfonyl, acyl, (C₁-C₆)alkyl-O—C(O)—, aryl, andheteroaryl, where said moiety is optionally substituted with one or moresubstituents; Z is —C(R^(4e))(R^(4e′)), where R^(4e) and R^(4e′) areeach independently hydrogen, H₂NC(O)—, or a chemical moiety selectedfrom (C₁-C₆)alkyl, (C₁-C₄)alkyl-NH—C(O)—, or ((C₁-C₄)alkyl)₂N—C(O)—,where said moiety is optionally substituted with one or moresubstituents, or either R^(4e) or R^(4e′) taken together with R^(4b),R^(4b′), R^(4c), or R^(4c′) forms a bond, a methylene bridge or anethylene bridge; a pharmaceutically acceptable salt thereof, or asolvate or hydrate of said compound or said salt.
 5. The compound ofclaim 4 wherein R^(4d″) is a hydrogen or a chemical moiety selected fromthe group consisting of (C₁-C₆)alkyl, (C₁-C₃)alkylsulfonyl,(C₁-C₃)alkylaminosulfonyl, di(C₁-C₃)alkylaminosulfonyl, acyl,(C₁-C₆)alkyl-O—C(O)—, and heteroaryl, where said moiety is optionallysubstituted with one or more substituents; a pharmaceutically acceptablesalt thereof, or a solvate or hydrate of said compound or said salt. 6.The compound of claim 5 wherein R^(4d″) is a hydrogen or a chemicalmoiety selected from the group consisting of (C₁-C₆)alkyl,(C₁-C₃)alkylsulfonyl, (C₁-C₃)alkylaminosulfonyl,di(C₁-C₃)alkylaminosulfonyl, acyl, and (C₁-C₆)alkyl-O—C(O)—, where saidmoiety is optionally substituted with 1-3 fluorines, or R^(4d″) is aheteroaryl, where said heteroaryl is optionally substituted with 1 to 2substituents independently selected from the group consisting of chloro,fluoro, (C₁-C₃)alkoxy, (C₁-C₃)alkyl, and fluoro-substituted(C₁-C₃)alkyl; a pharmaceutically acceptable salt thereof, or a solvateor hydrate of said compound or said salt.
 7. The compound of claim 4, 5or 6 wherein R⁰ and R¹ are each independently a phenyl substituted with1 to 3 substituents independently selected from the group consisting ofhalo, (C₁-C₄)alkoxy, (C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl, andcyano; a pharmaceutically acceptable salt thereof, or a solvate orhydrate of said compound or said salt.
 8. The compound of claim 7wherein R⁰ and R¹ are each independently a phenyl substituted with 1 to2 substituents independently selected from the group consisting ofchloro, fluoro, (C₁-C₄)alkoxy, (C₁-C₄)alkyl, fluoro-substituted(C₁-C₄)alkyl), and cyano; a pharmaceutically acceptable salt thereof, ora solvate or hydrate of said compound or said salt.
 9. The compound ofclaim 8 wherein R⁰ is 2-chlorophenyl, 2-fluorophenyl,2,4-dichlorophenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, or2,4-difluorophenyl; and R¹ is 4-chlorophenyl or 4-fluorophenyl; apharmaceutically acceptable salt thereof, or a solvate or hydrate ofsaid compound or said salt.
 10. The compound of claim 9 selected fromthe group consisting of3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-7-(4-methylpiperazin-1-yl)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(5-cyclopentyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2H-pyrazolo[4,3-d]pyrimidine;5-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester;5-[3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(5-methanesulfonyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-[5-(propane-2-sulfonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-[5-(2,2,2-trifluoroethanesulfonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2H-pyrazolo[4,3-d]pyrimidine;5-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-2,5-diazabicyclo[2.2.1]heptane-2-sulfonicacid dimethylamide;4-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-piperazine-1-sulfonicacid dimethylamide;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(4-ethanesulfonylpiperazin-1-yl)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(4-(2,2,2-trifluoroethane)sulfonylpiperazin-1-yl)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(4-methanesulfonylpiperazin-1-yl)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(4-(propane-2-sulfonyl)piperazin-1-yl)-2H-pyrazolo[4,3-d]pyrimidine;and3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-7-(4-methylpiperazin-1-yl)-2H-pyrazolo[3,4-c]pyridine;a pharmaceutically acceptable salt thereof, or a solvate or hydrate ofsaid compound or said salt.
 11. The compound of claim 3 wherein Y is—C(R^(4d))(R^(4d′))-, where R^(4d) is hydrogen, cyano, hydroxy, amino,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a partiallyor fully saturated carbocyclic ring, where said moiety is optionallysubstituted with one or more substituents, R^(4d′) is hydrogen,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6 membered partially orfully saturated heterocycle, and a partially or fully saturatedcarbocyclic ring, where said moiety is optionally substituted with oneor more substituents, or R^(4d) and R^(4d′) taken together form a 3-6membered partially or fully saturated carbocyclic ring, a 3-6 memberedpartially or fully saturated heterocyclic ring, a 5-6 membered lactonering, or a 4-6 membered lactam ring, where said carbocyclic ring, saidheterocyclic ring, said lactone ring and said lactam ring are optionallysubstituted with one or more substituents and said lactone ring and saidlactam ring optionally contain an additional heteroatom selected fromoxygen, nitrogen or sulfur; a pharmaceutically acceptable salt thereof,or a solvate or hydrate of said compound or said salt.
 12. The compoundof claim 11 wherein R^(4d) is amino, (C₁-C₆)alkylamino,di(C₁-C₄)alkylamino, azetidinyl, piperidinyl, pyrrolidinyl, morpholinyl,(C₃-C₆)cycloalkylamino, acylamino, aryl(C₁-C₄)alkylamino-,heteroaryl(C₁-C₄)alkylamino-, piperidinyl, pyrrolidinyl, or morpholinyl;and R^(4d′) is (C₁-C₆)alkyl, H₂NC(O)—, (C₁-C₄)alkyl-NH—C(O)—,((C₁-C₄)alkyl)₂N—C(O)—, or aryl; a pharmaceutically acceptable saltthereof, or a solvate or hydrate of said compound or said salt.
 13. Thecompound of claim 12 wherein R^(4d) is amino, (C₁-C₆)alkylamino,di(C₁-C₄)alkylamino, or (C₃-C₆)cycloalkylamino; and R^(4d′) is H₂NC(O)—,(C₁-C₄)alkyl-NH—C(O)—, or ((C₁-C₄)alkyl)₂N—C(O)—; a pharmaceuticallyacceptable salt thereof, or a solvate or hydrate of said compound orsaid salt.
 14. The compound of claim 11, 12, or 13 wherein R⁰ and R¹ areeach independently a phenyl substituted with 1 to 3 substituentsindependently selected from the group consisting of halo, (C₁-C₄)alkoxy,(C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl, and cyano; apharmaceutically acceptable salt thereof, or a solvate or hydrate ofsaid compound or said salt.
 15. The compound of claim 14 wherein R⁰ andR¹ are each independently a phenyl substituted with 1 to 2 substituentsindependently selected from the group consisting of chloro, fluoro,(C₁-C₄)alkoxy, (C₁-C₄)alkyl, fluoro-substituted (C₁-C₄)alkyl), andcyano; a pharmaceutically acceptable salt thereof, or a solvate orhydrate of said compound or said salt.
 16. The compound of claim 15wherein R⁰ is 2-chlorophenyl, 2-fluorophenyl, 2,4-dichlorophenyl,2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, or 2,4-difluorophenyl;and R¹ is 4-chlorophenyl or 4-fluorophenyl; a pharmaceuticallyacceptable salt thereof, or a solvate or hydrate of said compound orsaid salt.
 17. The compound of claim 16 selected from the groupconsisting of1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-ethylaminoazetidine-3-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-methylaminoazetidine-3-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-(2-propylamino)azetidine-3-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]4-isopropylaminopiperidine-4-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]4-ethylaminopiperidine-4-carboxylicacid amide;1′-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-[1,4′]bipiperidinyl-4′-carboxylicacid amide;8-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-pyrrolidin-1-yl-8-aza-bicyclo[3.2.1]octane-3-carboxylicacid amide;1′-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-[1,3′]bipyrrolidinyl-3′-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-morpholin-4-yl-pyrrolidine-3-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-isopropylaminopyrrolidine-3-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[3,4-c]pyridin-7-yl]4-isopropylaminopiperidine-4-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[3,4-c]pyridin-7-yl]-4-ethylaminopiperidine-4-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[3,4-c]pyridin-7-yl]-[1,4′]bipiperidinyl-4′-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[3,4-c]pyridin-7-yl]4-isopropylaminopiperidine-4-carboxylicacid amide; and1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[3,4-c]pyridin-7-yl]-3-ethylaminoazetidine-3-carboxylicacid amide; a pharmaceutically acceptable salt thereof or a solvate orhydrate of said compound or said salt.
 18. The compound of claim 17selected from the group consisting of1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-isopropylaminopiperidine-4-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-ethylaminopiperidine-4-carboxylicacid amide;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-isopropylaminopyrrolidine-3-carboxylicacid amide; and1′-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-[1,4′]bipiperidinyl-4′-carboxylicacid amide; a pharmaceutically acceptable salt thereof or a solvate orhydrate of said compound or said salt.
 19. The compound of claim 11wherein R^(4d) is hydrogen, hydroxy, amino, cyano or a chemical moietyselected from the group consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy,acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)-, (C₁-C₆)alkylamino-, anddi(C₁-C₄)alkylamino-, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,where said moiety is optionally substituted with one or moresubstituents; and R^(4d′) is hydrogen, or a chemical moiety selectedfrom the group consisting of (C₁-C₆)alkyl, aryl and heteroaryl, wheresaid moiety is optionally substituted with one or more substituents; apharmaceutically acceptable salt thereof, or a solvate or hydrate ofsaid compound or said salt.
 20. The compound of claim 19 wherein X is abond or —C(R^(4c))(R^(4c′))—, where R^(4c) and R^(4c′) are eachindependently hydrogen or an optionally substituted (C₁-C₆)alkyl, oreither R^(4c) or R^(4c′) taken together with R^(4e) or R^(4e′), forms abond, a methylene bridge or an ethylene bridge; and Z is a bond or—C(R^(4e))(R^(4e′))-, where R^(4e) and R^(4e′) are each independentlyhydrogen or an optionally substituted (C₁-C₆)alkyl, or either R^(4e) orR^(4e′) taken together with R^(4c) or R^(4c′) forms a bond, a methylenebridge or an ethylene bridge; a pharmaceutically acceptable saltthereof, or a solvate or hydrate of said compound or said salt.
 21. Thecompound of claim 20 wherein R^(4c) and R^(4c′) are each hydrogen oreither R^(4c) or R^(4c′) taken together with R^(4e) or R^(4e′) forms abond; R^(4d) is hydrogen, hydroxy, amino, cyano, or a chemical moietyselected from the group consisting of (C₁-C₆)alkoxy, acyl,(C₁-C₆)alkylamino-, (C₁-C₄)alkyl-NH—C(O)—(C₁-C₄)alkyl)₂N—C(O)—, anddi(C₁-C₄)alkylamino-; R^(4d′) is hydrogen, or a chemical moiety selectedfrom the group consisting of (C₁-C₆)alkyl and aryl, where said moiety isoptionally substituted with one or more substituents; and R^(4e) andR^(4e′) are hydrogen or either R^(4e) or R^(4e′) taken together withR^(4c) or R^(4c′) forms a bond; a pharmaceutically acceptable saltthereof, or a solvate or hydrate of said compound or said salt.
 22. Thecompound of claim 19, 20, or 21 wherein R⁰ and R¹ are each independentlya phenyl substituted with 1 to 3 substituents independently selectedfrom the group consisting of halo, (C₁-C₄)alkoxy, (C₁-C₄)alkyl,halo-substituted (C₁-C₄)alkyl, and cyano; a pharmaceutically acceptablesalt thereof, or a solvate or hydrate of said compound or said salt. 23.The compound of claim 22 wherein R⁰ and R¹ are each independently aphenyl substituted with 1 to 2 substituents independently selected fromthe group consisting of chloro, fluoro, (C₁-C₄)alkoxy, (C₁-C₄)alkyl,fluoro-substituted (C₁-C₄)alkyl), and cyano; a pharmaceuticallyacceptable salt thereof, or a solvate or hydrate of said compound orsaid salt.
 24. The compound of claim 23 wherein R⁰ is 2-chlorophenyl,2-fluorophenyl, 2,4-dichlorophenyl, 2-fluoro-4-chlorophenyl,2-chloro-4-fluorophenyl, or 2,4-difluorophenyl; and R¹ is 4-chlorophenylor 4-fluorophenyl; a pharmaceutically acceptable salt thereof, or asolvate or hydrate of said compound or said salt.
 25. The compound ofclaim 24 selected from the group consisting of1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]4-phenylpiperidin-4-ol;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-ethylpiperidin-4-ol;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-isopropylpiperidin-4-ol;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-sec-butylpiperidin-4-ol;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-methylpiperidin-4-ol;8-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-ethyl-8-azabicyclo[3.2.1]octan-3-ol;8-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-sec-butyl-8-azabicyclo[3.2.1]octan-3-ol;8-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-isopropyl-8-azabicyclo[3.2.1]octan-3-ol;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-isobutyl-pyrrolidin-3-ol;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-3-isopropyl-pyrrolidin-3-ol;{8-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-8-aza-bicyclo[3.2.1]oct-3-yl}-ethyl-amine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(3-pyrrolidin-1-yl-8-aza-bicyclo[3.2.1]oct-8-yl)-2H-pyrazolo[4,3-d]pyrimidine;7-(3-bromo-8-azabicyclo[3.2.1]oct-8-yl)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine;7-(3-bromo-8-azabicyclo[3.2.1]oct-8-yl)-3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(4-methylpiperidin-1-yl)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(3-hydroxypiperidin-1-yl)-2H-pyrazolo[4,3-d]pyrimidine;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-(3-methoxyphenyl)-piperidine-4-carbonitrile;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-phenylpiperidine-4-carbonitrile;1-{1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-phenylpiperidin-4-yl}-propan-1-one;1′-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-2′,3′,5′,6′-tetrahydro-1′H-[3,4′]bipyridinyl-4′-carbonitrile;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-2,3,5,6-tetrahydro-1H-[4,4′]bipyridinyl-4-carbonitrile;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-2,3,5,6-tetrahydro-1H-[2,4′]bipyridinyl-4-carbonitrile;{1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-4-phenylpiperidin-4-yl}-morpholin-4-yl-methanone;benzyl-{8-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-8-aza-bicyclo[3.2.1]oct-3-yl}-amine;{1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-pyrrolidin-3-yl}-methylcarbamicacid tert-butyl ester;{1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-pyrrolidin-3-yl}-carbamicacid tert-butyl ester;N-{1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-pyrrolidin-3-yl}-N-methylacetamide;and{1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-pyrrolidin-3-yl}-dimethylamine;a pharmaceutically acceptable salt thereof, or a solvate or hydrate ofsaid compound or said salt.
 26. The compound of claim 11 wherein R^(4b),R^(4b′), R^(4f), and R^(4f′) are all hydrogen; and R^(4d) and R^(4d′)taken together form a 3-6 membered partially or fully saturatedcarbocyclic ring, a 3-6 membered partially or fully saturatedheterocyclic ring, a 5-6 membered lactone ring, or a 4-6 membered lactamring, where said carbocyclic ring, said heterocyclic ring, said lactonering and said lactam ring are optionally substituted with one or moresubstituents and said lactone ring or said lactam ring optionallycontains an additional heteroatom selected from oxygen, nitrogen orsulfur; a pharmaceutically acceptable salt thereof, or a solvate orhydrate of said compound or said salt.
 27. The compound of claim 26wherein X is a bond, —CH₂CH₂— or —C(R^(4c))(R^(4c′))—, where R⁴ andR^(4c′) are each independently hydrogen or an optionally substituted(C₁-C₆)alkyl, or either R^(4c) or R^(4c′) taken together with R^(4e) orR^(4e′) forms a bond, a methylene bridge or an ethylene bridge; and Z isa bond, —CH₂CH₂— or —C(R^(4e))(R^(4e′))—, where R^(4e) and R^(4e′) areeach independently hydrogen or an optionally substituted (C₁-C₆)alkyl,or either R^(4e) or R^(4e′) taken together with R^(4c) or R^(4c′) formsa bond, a methylene bridge or an ethylene bridge; a pharmaceuticallyacceptable salt thereof, or a solvate or hydrate of said compound orsaid salt.
 28. The compound of claim 27 wherein R^(4d) and R^(4d′) takentogether form a 3-6 membered partially or fully saturated carbocyclicring, a 3-6 membered partially or fully saturated heterocyclic ring, ora 5-6 membered lactam ring, where said lactam ring is optionallysubstituted with one or more substituents and optionally contains anadditional heteroatom selected from nitrogen or oxygen; apharmaceutically acceptable salt thereof, or a solvate or hydrate ofsaid compound or said salt.
 29. The compound of claim 28 wherein X is abond or —C(R^(4c))(R^(4c′)), where R^(4c) and R^(4c′) are each hydrogen;and Z is a bond or C(R^(4e))(R^(4e′))-, where R^(4e) and R^(4e′) areeach hydrogen; a pharmaceutically acceptable salt thereof, or a solvateor hydrate of said compound or said salt.
 30. The compound of claim 26,27, 28 or 29 wherein R⁰ and R¹ are each independently a phenylsubstituted with 1 to 3 substituents independently selected from thegroup consisting of halo, (C₁-C₄)alkoxy, (C₁-C₄)alkyl, halo-substituted(C₁-C₄)alkyl, and cyano; a pharmaceutically acceptable salt thereof, ora solvate or hydrate of said compound or said salt.
 31. The compound ofclaim 30 wherein R⁰ and R¹ are each independently a phenyl substitutedwith 1 to 2 substituents independently selected from the groupconsisting of chloro, fluoro, (C₁-C₄)alkoxy, (C₁-C₄)alkyl,fluoro-substituted (C₁-C₄)alkyl), and cyano; a pharmaceuticallyacceptable salt thereof, or a solvate or hydrate of said compound orsaid salt.
 32. The compound of claim 31 wherein R⁰ is 2-chlorophenyl,2-fluorophenyl, 2,4-dichlorophenyl, 2-fluoro-4-chlorophenyl,2-chloro-4-fluorophenyl, or 2,4-difluorophenyl; and R¹ is 4-chlorophenylor 4-fluorophenyl; a pharmaceutically acceptable salt thereof, or asolvate or hydrate of said compound or said salt.
 33. The compound ofclaim 32 selected from the group consisting of2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-5-methyl-2,5,7-triaza-spiro[3.4]octan-8-one;8-[3-(4-chloro-phenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-1-isopropyl-1,3,8-triaza-spiro[4.5]decan-4-one;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2H-pyrazolo[4,3-d]pyrimidine;3-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-1-spiro[(5-methoxy)tetrahydronaphthalene-1,4′-piperidine];3-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-1-spiro[(6-methoxy)tetrahydronaphthalene-1,4′-piperidine];and3-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-1-spiro[indane-1,4′-piperidine];a pharmaceutically acceptable salt thereof or a solvate or hydrate ofsaid compound or said salt.
 34. The compound of claim 1 wherein R⁴ is agroup of Formula (IB)

where R^(4a) is as defined in claim 1; R^(4b) is hydrogen, cyano,hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a 3-6 membered partially or fully saturated heterocycle, anda partially or fully saturated carbocyclic ring, where said moiety isoptionally substituted with one or more substituents, R^(4b′) ishydrogen, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6membered partially or fully saturated heterocycle, and a partially orfully saturated carbocyclic ring, where said moiety is optionallysubstituted with one or more substituents, or R^(4b) or R^(4b′) takentogether with R^(4e), R^(4e′), R^(4f), or R^(4f′) forms a bond, amethylene bridge, or an ethylene bridge; X is a bond, —CH₂CH₂— or—C(R^(4c))(R^(4c′))—, where R^(4c) is hydrogen, cyano, hydroxy, amino,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a partiallyor fully saturated carbocyclic ring, where said moiety is optionallysubstituted with one or more substituents, or R^(4c) taken together withR^(4e), R^(4e′), R^(4f), or R^(4f′) forms a bond, a methylene bridge, oran ethylene bridge, and R^(4c′) is hydrogen, H₂NC(O)—, or a chemicalmoiety selected from the group consisting of (C₁-C₆)alkyl, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,aryl, heteroaryl, a 3-6 membered partially or fully saturatedheterocycle, and a partially or fully saturated carbocyclic ring, wheresaid moiety is optionally substituted with one or more substituents, orR^(4c′) taken together with R^(4e), R^(4e′), R^(4f), or R^(4f′) forms abond, a methylene bridge, or an ethylene bridge; Y is oxygen, sulfur,—C(O)—, or —C(R^(4d))(R^(4d′))—, where R^(4d) is hydrogen, cyano,hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a 3-6 membered partially or fully saturated heterocycle, anda partially or fully saturated carbocyclic ring, where said moiety isoptionally substituted with one or more substituents, and R^(4d′) ishydrogen, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6membered partially or fully saturated heterocycle, and a partially orfully saturated carbocyclic ring, where said moiety is optionallysubstituted with one or more substituents, or R^(4d) and R^(4d′) takentogether form a 3-6 membered partially or fully saturated carbocyclicring, a 3-6 membered partially or fully saturated heterocyclic ring, a5-6 membered lactone ring, or a 4-6 membered lactam ring, where saidcarbocyclic ring, said heterocyclic ring, said lactone ring and saidlactam ring are optionally substituted with one or more substituents andsaid lactone ring and said lactam ring optionally contain an additionalheteroatom selected from oxygen, nitrogen or sulfur; Y is —NR^(4d″)—,where R^(4d″) is a hydrogen or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₃)alkylsulfonyl-,(C₁-C₃)alkylaminosulfonyl-, di(C₁-C₃)alkylaminosulfonyl-, acyl,(C₁-C₆)alkyl-O—C(O)—, aryl, and heteroaryl, where said moiety isoptionally substituted with one or more substituents; Z is a bond,—CH₂CH₂—, or —C(R^(4e))(R^(4e′))—, where R^(4e) is hydrogen, cyano,hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-aryl,heteroaryl, a 3-6 membered partially or fully saturated heterocyclicring, and a partially or fully saturated carbocyclic ring, where saidmoiety is optionally substituted with one or more substituents, orR^(4e) taken together with R^(4b), R^(4b′), R^(4c), or R^(4c′) forms abond, a methylene bridge, or an ethylene bridge, and R^(4e′) ishydrogen, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6membered partially or fully saturated heterocycle, and a partially orfully saturated carbocyclic ring, where said moiety is optionallysubstituted with one or more substituents, or R^(4e′) taken togetherwith R^(4b), R^(4b′), R^(4c), or R^(4c′) forms a bond, a methylenebridge, or an ethylene bridge; R^(4f) is hydrogen, cyano, hydroxy,amino, H₂NC(O)—, or a chemical moiety selected from the group consistingof (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a partiallyor fully saturated carbocyclic ring, where said moiety is optionallysubstituted with one or more substituents; and R^(4f) is hydrogen,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6 membered partially orfully saturated heterocycle, and a partially or fully saturatedcarbocyclic ring, where said moiety is optionally substituted with oneor more substituents, or R⁴ or R^(4f′) taken together with R^(4b),R^(4b′), R^(4c), or R^(4c′) forms a bond, a methylene bridge, or anethylene bridge; a pharmaceutically acceptable salt thereof, or asolvate or hydrate of said compound or said salt.
 35. The compound ofclaim 34 wherein R⁰ and R¹ are each independently a substituted phenyl;R^(4a), R^(4b), R^(4b′), R^(4f) and R^(4f′) are each hydrogen; apharmaceutically acceptable salt thereof, or a solvate or hydrate ofsaid compound or said salt.
 36. The compound of claim 35 wherein X is abond, —CH₂CH₂— or —C(R^(4c))(R^(4c′))—, where R^(4c) and R^(4c′) areeach independently hydrogen or (C₁-C₆)alkyl; Y is —NR^(4d″)—, whereR^(4d″) is hydrogen or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₃)alkylsulfonyl-,(C₁-C₃)alkylaminosulfonyl-, di(C₁-C₃)alkylaminosulfonyl-, acyl,(C₁-C₆)alkyl-O—C(O)—, aryl, and heteroaryl, where said moiety isoptionally substituted with one or more substituents; Z is a bond,—CH₂CH₂— or —C(R^(4c))(R^(4c′))—, where R^(4c) and R^(4c′) are eachindependently hydrogen or (C₁-C₆)alkyl; a pharmaceutically acceptablesalt thereof, or a solvate or hydrate of said compound or said salt. 37.The compound of claim 35 or 36 wherein R⁰ and R¹ are each independentlya phenyl substituted with 1 to 3 substituents independently selectedfrom the group consisting of halo, (C₁-C₄)alkoxy, (C₁-C₄)alkyl,halo-substituted (C₁-C₄)alkyl, and cyano; a pharmaceutically acceptablesalt thereof, or a solvate or hydrate of said compound or said salt. 38.The compound of claim 37 wherein R⁰ and R¹ are each independently aphenyl substituted with 1 to 2 substituents independently selected fromthe group consisting of chloro, fluoro, (C₁-C₄)alkoxy, (C₁-C₄)alkyl,fluoro-substituted (C₁-C₄)alkyl), and cyano; a pharmaceuticallyacceptable salt thereof, or a solvate or hydrate of said compound orsaid salt.
 39. The compound of claim 38 wherein R⁰ is 2-chlorophenyl,2-fluorophenyl, 2,4-dichlorophenyl, 2-fluoro-4-chlorophenyl,2-chloro-4-fluorophenyl, or 2,4-difluorophenyl; and R¹ is 4-chlorophenylor 4-fluorophenyl; a pharmaceutically acceptable salt thereof, or asolvate or hydrate of said compound or said salt.
 40. The compound ofclaim 39 selected from the group consisting of7-(1-benzhydrylazetidin-3-yloxy)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine;and7-(1-benzylpyrrolidin-3-yloxy)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine;a pharmaceutically acceptable salt thereof or a solvate or hydrate ofsaid compound or said salt.
 41. The compound of claim 1 wherein R⁴ is agroup of Formula (IC)

where R⁵ and R⁶ are each independently hydrogen, aryl, or (C₁-C₄)alkyl,and R⁷ is an optionally substituted (C₁-C₄)alkyl-, or an optionallysubstituted 4-6 membered partially or fully saturated heterocylic ringcontaining 1 to 2 heteroatoms independently selected from oxygen, sulfuror nitrogen, or R⁵ and R⁶ or R⁵ and R⁷ taken together form a 5-6membered lactone, 4-6 membered lactam, or a 4-6 membered partially orfully saturated heterocycle containing 1 to 2 heteroatoms independentlyselected from oxygen, sulfur or nitrogen, where said lactone, saidlactam and said heterocycle are optionally substituted with one or moresubstituents; a pharmaceutically acceptable salt thereof, or a solvateor hydrate of said compound or said salt.
 42. The compound of claim 41wherein R⁰ and R¹ are each independently a substituted phenyl; apharmaceutically acceptable salt thereof, or a solvate or hydrate ofsaid compound or said salt.
 43. The compound of claim 41 or 42 whereinR⁰ and R¹ are each independently a phenyl substituted with 1 to 3substituents independently selected from the group consisting of halo,(C₁-C₄)alkoxy, (C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl, and cyano; apharmaceutically acceptable salt thereof, or a solvate or hydrate ofsaid compound or said salt.
 44. The compound of claim 43 wherein R⁰ andR¹ are each independently a phenyl substituted with 1 to 2 substituentsindependently selected from the group consisting of bromo, chloro,fluoro, (C₁-C₄)alkoxy, (C₁-C₄)alkyl, fluoro-substituted (C₁-C₄)alkyl),and cyano; a pharmaceutically acceptable salt thereof, or a solvate orhydrate of said compound or said salt.
 45. The compound of claim 44selected from the group consisting of2-(2-chlorophenyl)-7-isopropoxy-3-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-d]pyrimidine;2-(2-chloro-4-methylphenyl)-5-methyl-7-(2,2,2-trifluoroethoxy)-3-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-d]pyrimidine;2-(2-chlorophenyl)-3-(4-methoxyphenyl)-5-methyl-7-(2,2,2-trifluoroethoxy)-2H-pyrazolo[4,3-d]pyrimidine;2-(2-bromophenyl)-3-(4-chlorophenyl)-7-(2,2-difluoropropoxy)-5-methyl-2H-pyrazolo[4,3-d]pyrimidine;2-(2-bromophenyl)-3-(4-methoxyphenyl)-5-methyl-7-(2,2,2-trifluoroethoxy)-2H-pyrazolo[4,3-d]pyrimidine;2-[3-(4-chlorophenyl)-7-(2,2-difluoropropoxy)-5-methylpyrazolo[4,3-d]pyrimidin-2-yl]-benzonitrile;2-(2-bromophenyl)-7-(2,2-difluoropropoxy)-3-(4-methoxyphenyl)-5-methyl-2H-pyrazolo[4,3-d]pyrimidine;3-(4-bromophenyl)-2-(2-chlorophenyl)-7-(2,2-difluoropropoxy)-5-methyl-2H-pyrazolo[4,3-d]pyrimidine;and2-(2-chlorophenyl)-7-(2,2-difluoropropoxy)-3-(4-methoxyphenyl)-5-methyl-2H-pyrazolo[4,3-d]pyrimidine;a pharmaceutically acceptable salt thereof or a solvate or hydrate ofsaid compound or said salt.
 46. The compound of claim 44 wherein R⁰ is2-chlorophenyl, 2-fluorophenyl, 2,4-dichlorophenyl,2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, or 2,4-difluorophenyl;and R¹ is 4-chlorophenyl or 4-fluorophenyl; a pharmaceuticallyacceptable salt thereof, or a solvate or hydrate of said compound orsaid salt.
 47. The compound of claim 46 selected from the groupconsisting of3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-isopropoxy-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(2,2,2-trifluoroethoxy)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-methoxy-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-ethoxy-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-propoxy-2H-pyrazolo[4,3-d]pyrimidine;7-butoxy-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-5-ethyl-7-(2,2,2-trifluoroethoxy)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-5-isopropyl-7-(2,2,2-trifluoroethoxy)-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-ethoxy-5-trifluoromethyl-2H-pyrazolo[4,3-d]pyrimidine;3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(2,2,2-trifluoroethoxy)-5-trifluoromethyl-2H-pyrazolo[4,3-d]pyrimidine;and3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(2,2-difluorobutoxy)-5-methyl-2H-pyrazolo[4,3-d]pyrimidine;a pharmaceutically acceptable salt thereof or a solvate or hydrate ofsaid compound or said salt.
 48. The compound of claim 1 wherein R⁴ is anamino group having attached thereto at least one chemical moietyselected from the group consisting of (C₁-C₈)alkyl, aryl,aryl(C₁-C₄)alkyl, a 3-8 membered partially or fully saturatedcarbocyclic ring, hydroxy(C₁-C₆)alkyl, (C₁-C₃)alkoxy(C₁-C₆)alkyl,heteroaryl(C₁-C₃)alkyl, and a fully or partially saturated heterocycle,where said chemical moiety is optionally substituted with one or moresubstituents; a pharmaceutically acceptable salt thereof, or a solvateor hydrate of said compound or said salt.
 49. The compound of claim 48wherein R⁰ and R¹ are each independently a substituted phenyl; apharmaceutically acceptable salt thereof, or a solvate or hydrate ofsaid compound or said salt.
 50. The compound of claim 48 or 49 whereinR⁰ and R¹ are each independently a phenyl substituted with 1 to 3substituents independently selected from the group consisting of halo,(C₁-C₄)alkoxy, (C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl, and cyano; apharmaceutically acceptable salt thereof, or a solvate or hydrate ofsaid compound or said salt.
 51. The compound of claim 50 wherein R⁰ andR¹ are each independently a phenyl substituted with 1 to 2 substituentsindependently selected from the group consisting of chloro, fluoro,(C₁-C₄)alkoxy, (C₁-C₄)alkyl, fluoro-substituted (C₁-C₄)alkyl, and cyano;a pharmaceutically acceptable salt thereof, or a solvate or hydrate ofsaid compound or said salt.
 52. The compound of claim 51 wherein R⁰ is2-chlorophenyl, 2-fluorophenyl, 2,4-dichlorophenyl,2-fluoro-4-chlorophenyl, 2-chloro-4-fluorophenyl, or 2,4-difluorophenyl;and R¹ is 4-chlorophenyl or 4-fluorophenyl; a pharmaceuticallyacceptable salt thereof, or a solvate or hydrate of said compound orsaid salt.
 53. The compound of claim 52 selected from the groupconsisting ofN4-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-N,N-diethylpentane-1,4-diamine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(1-methyl-2-morpholin-4-yl-ethyl)-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-pyridin-2-yl-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(5-methylpyridin-2-yl)-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(5-methoxypyridin-2-yl)-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-amine;(6-azetidin-1-yl-pyridin-3-yl)-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-pyridin-2-ylmethylamine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(5-methyl-pyridin-2-ylmethyl)-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-pyridin-3-ylmethylamine;[3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-diethylamine;bicyclo[2.2.1]hept-2-yl-[3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-cyclohexylamine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-diethylamine;bicyclo[2.2.1]hept-2-yl-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(4-methyl-cyclohexyl)amine;adamantan-2-yl-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(3-methylcyclohexyl)amine;2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]cyclopentanecarboxylicacid ethyl ester;2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]cyclopentanol;2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]cyclohexanol;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(2,6-dimethylcyclohexyl)amine;5[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]cycloheptylamine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]cyclobutylamine;2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]-2-methylpropane-1,3-diol;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(1-methyl-1-phenylethyl)amine;{1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]cyclopentyl}methanol;2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]-2-methylpropan-1-ol;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(1,1-dimethylpropyl)amine;2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]-3-phenylpropan-1-ol;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-indan-2-ylamine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(1,2,3,4-tetrahydronaphthalen-1-yl)amine;2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]-1-pyrrolidin-1-ylpropan-1-one;4-{2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]propyl}phenol;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(1-cyclohexylethyl)amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(1-p-tolylethyl)amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(2-phenylcyclopropyl)amine;2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]indan-1-ol;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(2-morpholin-4-yl-ethyl)amine;(1H-Benzoimidazol-2-ylmethyl)-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-amine;1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]propan-2-ol;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(2,2,2-trifluoroethyl)amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-cyclopropylmethylamine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(1-cyclohexylethyl)amine;and3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-7-pyrrolidin-1-yl-2H-pyrazolo[3,4-c]pyridine;a pharmaceutically acceptable salt thereof or a solvate or hydrate ofsaid compound or said salt.
 54. The compound of claim 53 selected fromthe group consisting of[3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-diethylamine;bicyclo[2.2.1]hept-2-yl-[3-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-diethylamine;bicyclo[2.2.1]hept-2-yl-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-amine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-cyclohexylamine;adamantan-2-yl-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-amine;2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]cyclohexanol;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]cyclobutylamine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(1-methyl-1-phenylethyl)amine;{1-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]cyclopentyl}methanol;2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]-3-phenylpropan-1-ol;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-indan-2-ylamine;[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-yl]-(1-cyclohexylethyl)amine;and2-[3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ylamino]indan-1-ol;a pharmaceutically acceptable salt thereof or a solvate or hydrate ofsaid compound or said salt.
 55. A compound of Formula (II)

wherein A is N or C(R²), where R² is hydrogen, (C₁-C₄)alkyl,halo-substituted (C₁-C₄)alkyl, or (C₁-C₄)alkoxy; R^(0a), R^(0b), R^(1a),and R^(1b) are each independently halo, (C₁-C₄)alkoxy, (C₁-C₄)alkyl,halo-substituted (C₁-C₄)alkyl, or cyano; n and m are each independently0, 1 or 2; R³ is hydrogen, (C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl,or (C₁-C₄)alkoxy; R⁴ is (i) a group having Formula (IA) or Formula (IB)

 where R^(4a) is hydrogen or (C₁-C₃)alkyl; R^(4b) and R^(4b′) are eachindependently hydrogen, cyano, hydroxy, amino, H₂NC(O)—, or a chemicalmoiety selected from the group consisting of (C₁-C₆)alkyl,(C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a partiallyor fully saturated carbocyclic ring, where the moiety is optionallysubstituted with one or more substituents, or either R^(4b) or R^(4b′)taken together with R^(4e), R^(4e′), R^(4f), or R^(4f′) forms a bond, amethylene bridge, or an ethylene bridge; X is a bond, —CH₂CH₂— or—C(R^(4c))(R^(4c′))—, where R^(4c) and R^(4c′) are each independentlyhydrogen, cyano, hydroxy, amino, H₂NC(O)—, or a chemical moiety selectedfrom the group consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, ((C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a 3-6 membered partially or fully saturated heterocycle, anda 3-6 membered partially or fully saturated carbocyclic ring, where themoiety is optionally substituted with one or more substituents, oreither R^(4c) or R^(4c′) taken together with R^(4e), R^(4e′), R^(4f), orR^(4f′) forms a bond, a methylene bridge or an ethylene bridge; Y isoxygen, sulfur, —C(O)—, or —C(R^(4d))(R^(4d′))—, where R^(4d) andR^(4d′) are each independently hydrogen, cyano, hydroxy, amino,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, ((C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a 3-6membered partially or fully saturated carbocyclic ring, where the moietyis optionally substituted with one or more substituents, or R^(4d) andR^(4d′) taken together form a 3-6 membered partially or fully saturatedcarbocyclic ring, a 3-6 membered partially or fully saturatedheterocyclic ring, a 5-6 membered lactone ring, or a 4-6 membered lactamring, where said carbocyclic ring, said heterocyclic ring, said lactonering and said lactam ring are optionally substituted with one or moresubstituents and said lactone ring and said lactam ring optionallycontain an additional heteroatom selected from oxygen, nitrogen orsulfur, or Y is —NR^(4d″)—, where R^(4d″) is a hydrogen or a chemicalmoiety selected from the group consisting of (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₁-C₃)alkylsulfonyl-, (C₁-C₃)alkylaminosulfonyl-,di(C₁-C₃)alkylaminosulfonyl-, acyl, (C₁-C₆)alkyl-O—C(O)—, aryl, andheteroaryl, where the moiety is optionally substituted with one or moresubstituents; Z is a bond, —CH₂CH₂—, or —C(R^(4e))(R^(4e′))—, whereR^(4e) and R^(4e′) are each independently hydrogen, cyano, hydroxy,amino, H₂NC(O)—, or a chemical moiety selected from the group consistingof (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, ((C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocyclic ring, and a 3-6membered partially or fully saturated carbocyclic ring, where the moietyis optionally substituted with one or more substituents, or eitherR^(4e) or R^(4e′) taken together with R^(4b), R^(4b′), R^(4c), orR^(4c′) forms a bond, a methylene bridge or an ethylene bridge; andR^(4f) and R^(4f′) are each independently hydrogen, cyano, hydroxy,amino, H₂NC(O)—, or a chemical moiety selected from the group consistingof (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, ((C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,di(C₁-C₄)alkylamino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a 3-6membered partially or fully saturated carbocyclic ring, where the moietyis optionally substituted with one or more substituents, or eitherR^(4f) or R^(4f′) taken together with R^(4b), R^(4b′), R^(4c), orR^(4c′) forms a bond, a methylene bridge or an ethylene bridge; (ii) agroup having Formula (IC)

where R⁵ and R⁶ are each independently hydrogen, aryl, or (C₁-C₄)alkyl,and R⁷ is an optionally substituted (C₁-C₄)alkyl-, or an optionallysubstituted 4-6 membered partially or fully saturated heterocylic ringcontaining 1 to 2 heteroatoms independently selected from oxygen, sulfuror nitrogen, or R⁵ and R⁶ or R⁵ and R⁷ taken together form a 5-6membered lactone, 4-6 membered lactam, or a 4-6 membered partially orfully saturated heterocycle containing 1 to 2 heteroatoms independentlyselected from oxygen, sulfur or nitrogen, where said lactone, saidlactam and said heterocycle are optionally substituted with one or moresubstituents; (iii) an amino group having attached thereto at least onechemical moiety selected from the group consisting of (C₁-C₈)alkyl,aryl, aryl(C₁-C₄)alkyl, a 3-8 membered partially or fully saturatedcarbocyclic ring, hydroxy(C₁-C₆)alkyl, (C₁-C₃)alkoxy(C₁-C₆)alkyl,heteroaryl(C₁-C₃)alkyl, and a fully or partially saturated heterocycle,where said chemical moiety is optionally substituted with one or moresubstituents; or (iv) an (C₁-C₆)alkyl group having attached thereto atleast one chemical moiety selected from the group consisting of hydroxy,(C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino,di((C₁-C₆)alkyl)amino(C₁-C₃)alkylsulfonyl, (C₁-C₃)alkylsulfamyl,di((C₁-C₃)alkyl)sulfamyl, acyloxy, a fully or partially saturatedheterocycle, and a fully or partially saturated carbocyclic ring, wheresaid chemical moiety is optionally substituted with one or moresubstituents; a pharmaceutically acceptable salt thereof, a prodrug ofsaid compound or said salt, or a solvate or hydrate of said compound,said salt or said prodrug.
 56. The compound of claim 55 wherein R⁴ is agroup of Formula (IA);

where, R^(4b) and R^(4b′) are each independently hydrogen, H₂NC(O)—, ora chemical moiety selected from the group consisting of (C₁-C₆)alkyl,acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a partially or fully saturatedheterocycle, and a 3-6 membered partially or fully saturated carbocyclicring, where said moiety is optionally substituted with one or moresubstituents, or R^(4b) or R^(4b′) taken together with R^(4e), R^(4e′),R^(4f), or R^(4f′) forms a bond, a methylene bridge, or an ethylenebridge; X is a bond, —CH₂CH₂— or —C(R^(4c))(R^(4c′))—, where R^(4c) ishydrogen, cyano, hydroxy, amino, H₂NC(O)—, or a chemical moiety selectedfrom the group consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a 3-6 membered partially or fully saturated heterocycle, anda partially or fully saturated carbocyclic ring, where said moiety isoptionally substituted with one or more substituents, or R^(4c) takentogether with R^(4e), R^(4e′), R^(4f), or R^(4f′) forms a bond, amethylene bridge, or an ethylene bridge, and R^(4c′) is hydrogen,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6 membered partially orfully saturated heterocycle, and a partially or fully saturatedcarbocyclic ring, where said moiety is optionally substituted with oneor more substituents, or R^(4c′) taken together with R^(4e), R^(4e′),R^(4f), or R^(4f′) forms a bond, a methylene bridge, or an ethylenebridge; Y is oxygen, sulfur, —C(O)—, or —C(R^(4d))(R^(4d′))—, whereR^(4d) is hydrogen, cyano, hydroxy, amino, H₂NC(O)—, or a chemicalmoiety selected from the group consisting of (C₁-C₆)alkyl,(C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a partiallyor fully saturated carbocyclic ring, where said moiety is optionallysubstituted with one or more substituents, and R^(4d′) is hydrogen,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6 membered partially orfully saturated heterocycle, and a partially or fully saturatedcarbocyclic ring, where said moiety is optionally substituted with oneor more substituents, or R^(4d) and R^(4d′) taken together form a 3-6membered partially or fully saturated carbocyclic ring, a 3-6 memberedpartially or fully saturated heterocyclic ring, a 5-6 membered lactonering, or a 4-6 membered lactam ring, where said carbocyclic ring, saidheterocyclic ring, said lactone ring and said lactam ring are optionallysubstituted with one or more substituents and said lactone ring and saidlactam ring optionally contain an additional heteroatom selected fromoxygen, nitrogen or sulfur, or Y is —NR^(4d″)—, where R^(4d″) is ahydrogen or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₃)alkylsulfonyl-,(C₁-C₃)alkylaminosulfonyl-, di(C₁-C₃)alkylaminosulfonyl-, acyl,(C₁-C₆)alkyl-O—C(O)—, aryl, and heteroaryl, where said moiety isoptionally substituted with one or more substituents; Z is a bond,—CH₂CH₂—, or —C(R^(4e))(R^(4e′))—, where R^(4e) is hydrogen, cyano,hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a 3-6 membered partially or fully saturated heterocycle, anda partially or fully saturated carbocyclic ring, where said moiety isoptionally substituted with one or more substituents, or R^(4e) takentogether with R^(4b), R^(4b′), R^(4c), or R^(4c′) forms a bond, amethylene bridge, or an ethylene bridge, and R^(4e′) is hydrogen,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6 membered partially orfully saturated heterocycle, and a partially or fully saturatedcarbocyclic ring, where said moiety is optionally substituted with oneor more substituents, or R^(4e′) taken together with R^(4b), R^(4b′),R^(4c), or R^(4c′) forms a bond, a methylene bridge, or an ethylenebridge; and R^(4f) and R^(4f′) are each independently hydrogen,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6 membered partially orfully saturated heterocycle, and a partially or fully saturatedcarbocyclic ring, where said moiety is optionally substituted with oneor more substituents, or R^(4f) or R^(4f′) taken together with R^(4b),R^(4b′), R^(4c), or R^(4c′) forms a bond, a methylene bridge, or anethylene bridge; a pharmaceutically acceptable salt thereof, or asolvate or hydrate of said compound or said salt.
 57. The compound ofclaim of 56 wherein R^(4b) is hydrogen, an optionally substituted(C₁-C₃)alkyl, or taken together with R^(4e), R^(4e′), R^(4f), or R^(4f′)forms a bond, a methylene bridge, or an ethylene bridge; R^(4b′) ishydrogen, an optionally substituted (C₁-C₃)alkyl, or taken together withR^(4e), R^(4e′), R^(4f), or R^(4f′) forms a bond, a methylene bridge, oran ethylene bridge; R^(4f) is hydrogen, an optionally substituted(C₁-C₃)alkyl, or taken together with R^(4b), R^(4b′), R^(4c), or R^(4c′)forms a bond, a methylene bridge, or an ethylene bridge; and R^(4f) ishydrogen, an optionally substituted (C₁-C₃)alkyl, or taken together withR^(4b), R^(4b′), R^(4c), or R^(4c′) forms a bond, a methylene bridge, oran ethylene bridge; a pharmaceutically acceptable salt thereof, or asolvate or hydrate of said compound or said salt.
 58. The compound ofclaim 57 wherein X is —C(R^(4c))(R^(4c′))—, where R^(4c) and R^(4c′) areeach independently hydrogen, H₂NC(O)—, or a chemical moiety selectedfrom (C₁-C₆)alkyl, (C₁-C₄)alkyl-NH—C(O)—, or ((C₁-C₄)alkyl)₂N—C(O)—,where said moiety is optionally substituted with one or moresubstituents, or either R^(4c) or R^(4c′) taken together with R^(4e),R^(4e′), R^(4f), or R^(4f′) forms a bond, a methylene bridge or anethylene bridge; Y is —NR^(4d″)—, where R^(4d″) is a hydrogen or achemical moiety selected from the group consisting of (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₁-C₃)alkylsulfonyl, (C₁-C₃)alkylaminosulfonyl,di(C₁-C₃)alkylaminosulfonyl, acyl, (C₁-C₆)alkyl-O—C(O)—, aryl, andheteroaryl, where said moiety is optionally substituted with one or moresubstituents; Z is —C(R^(4e))(R^(4e′))—, where R^(4e) and R^(4e′) areeach independently hydrogen, H₂NC(O)—, or a chemical moiety selectedfrom (C₁-C₆)alkyl, (C₁-C₄)alkyl-NH—C(O)—, or ((C₁-C₄)alkyl)₂N—C(O)—,where said moiety is optionally substituted with one or moresubstituents, or either R^(4e) or R^(4e′) taken together with R^(4b),R^(4b′), R^(4c), or R^(4c′) forms a bond, a methylene bridge or anethylene bridge; a pharmaceutically acceptable salt thereof, or asolvate or hydrate of said compound or said salt.
 59. The compound ofclaim 58 wherein R^(4d″) is a hydrogen or a chemical moiety selectedfrom the group consisting of (C₁-C₃)alkylsulfonyl,(C₁-C₃)alkylaminosulfonyl, di(C₁-C₃)alkylaminosulfonyl, acyl,(C₁-C₆)alkyl-O—C(O)—, and heteroaryl, where said moiety is optionallysubstituted with one or more substituents; a pharmaceutically acceptablesalt thereof, or a solvate or hydrate of said compound or said salt. 60.The compound of claim 59 wherein R^(4d″) is a hydrogen or a chemicalmoiety selected from the group consisting of (C₁-C₃)alkylsulfonyl,(C₁-C₃)alkylaminosulfonyl, di(C₁-C₃)alkylaminosulfonyl, acyl, and(C₁-C₆)alkyl-O—C(O)—, where said moiety is optionally substituted with1-3 fluorines, or R^(d″) is a heteroaryl, where said heteroaryl isoptionally substituted with 1 to 2 substituents independently selectedfrom the group consisting of chloro, fluoro, (C₁-C₃)alkoxy,(C₁-C₃)alkyl, and fluoro-substituted (C₁-C₃)alkyl; a pharmaceuticallyacceptable salt thereof, or a solvate or hydrate of said compound orsaid salt.
 61. The compound of claim 58, 59, or 60 wherein R^(0a),R^(0a), R^(1a) and R^(1b) are each independently selected from the groupconsisting of halo, (C₁-C₄)alkoxy, (C₁-C₄)alkyl, halo-substituted(C₁-C₄)alkyl, and cyano; a pharmaceutically acceptable salt thereof, ora solvate or hydrate of said compound or said salt.
 62. The compound ofclaim 61 wherein R^(0a), R^(0a), R^(1a) and R^(1b) are eachindependently selected from the group consisting of chloro, fluoro,(C₁-C₄)alkoxy, (C₁-C₄)alkyl, fluoro-substituted (C₁-C₄)alkyl), andcyano; and n and m are each independently 0 or 1; a pharmaceuticallyacceptable salt thereof, a prodrug of said compound or said salt, or asolvate or hydrate of said compound, said salt or said prodrug.
 63. Thecompound of claim 57 wherein Y is —C(R^(4d))(R^(4d′))—, where R^(4d) ishydrogen, cyano, hydroxy, amino, H₂NC(O)—, or a chemical moiety selectedfrom the group consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a 3-6 membered partially or fully saturated heterocycle, anda partially or fully saturated carbocyclic ring, where said moiety isoptionally substituted with one or more substituents, R^(4d′) ishydrogen, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6membered partially or fully saturated heterocycle, and a partially orfully saturated carbocyclic ring, where said moiety is optionallysubstituted with one or more substituents, or R^(4d) and R^(4d′) takentogether form a 3-6 membered partially or fully saturated carbocyclicring, a 3-6 membered partially or fully saturated heterocyclic ring, a5-6 membered lactone ring, or a 4-6 membered lactam ring, where saidcarbocyclic ring, said heterocyclic ring, said lactone ring and saidlactam ring are optionally substituted with one or more substituents andsaid lactone ring and said lactam ring optionally contain an additionalheteroatom selected from oxygen, nitrogen or sulfur; a pharmaceuticallyacceptable salt thereof, or a solvate or hydrate of said compound orsaid salt.
 64. The compound of claim 63 wherein R^(4b), R^(4b′), R^(4f),and R^(4f′) are all hydrogen; R^(4d) is amino, (C₁-C₆)alkylamino,di(C₁-C₄)alkylamino, (C₃-C₆)cycloalkylamino, acylamino,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-; and R^(4d′) is(C₁-C₆)alkyl, H₂NC(O)—, (C₁-C₄)alkyl-NH—C(O)—, or((C₁-C₄)alkyl)₂N—C(O)—, or aryl; a pharmaceutically acceptable saltthereof, or a solvate or hydrate of said compound or said salt.
 65. Thecompound of claim 64 wherein X is a bond or —C(R⁴)(R^(4c′))—, whereR^(4c) and R^(4c′) are each hydrogen; and Z is a bond orC(R^(4e))(R^(4e′))—, where R^(4e) and R^(4e′) are each hydrogen; apharmaceutically acceptable salt thereof, or a solvate or hydrate ofsaid compound or said salt.
 66. The compound of claim 65 wherein R^(4d)is amino, (C₁-C₆)alkylamino, di(C₁-C₄)alkylamino,(C₃-C₆)cycloalkylamino; and R^(4d′) is H₂NC(O)—, (C₁-C₄)alkyl-NH—C(O)—,or ((C₁-C₄)alkyl)₂N—C(O)—; a pharmaceutically acceptable salt thereof,or a solvate or hydrate of said compound or said salt.
 67. The compoundof claim 63, 64, 65 or 66 wherein R^(0a), R^(0b), R^(1a), and R^(1b) areeach independently selected from the group consisting of halo,(C₁-C₄)alkoxy, (C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl, and cyano; apharmaceutically acceptable salt thereof, or a solvate or hydrate ofsaid compound or said salt.
 68. The compound of claim 67 wherein R^(0a),R^(0b), R^(1a), and R^(1b) are each independently selected from thegroup consisting of chloro, fluoro, (C₁-C₄)alkoxy, (C₁-C₄)alkyl,fluoro-substituted (C₁-C₄)alkyl), and cyano; and n and m are eachindependently selected from 0 or 1; a pharmaceutically acceptable saltthereof, or a solvate or hydrate of said compound or said salt.
 69. Thecompound of claim 63 wherein R^(4b), R^(4b′), R^(4f), and R^(4f′) areall hydrogen; R^(4d) is hydrogen, hydroxy, amino, or a chemical moietyselected from the group consisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy,acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₆)alkylamino-, anddi(C₁-C₄)alkylamino-, where said moiety is optionally substituted withone or more substituents; and R^(4d′) is hydrogen, or a chemical moietyselected from the group consisting of (C₁-C₆)alkyl, aryl and heteroaryl,where said moiety is optionally substituted with one or moresubstituents; a pharmaceutically acceptable salt thereof, or a solvateor hydrate of said compound or said salt.
 70. The compound of claim 69wherein X is a bond or —C(R^(4c))(R^(4c′))—, where R^(4c) and R^(4c′)are each independently hydrogen or an optionally substituted(C₁-C₆)alkyl, or either R^(4c) or R^(4c′) taken together with R^(4e) orR^(4e′) forms a bond, a methylene bridge or an ethylene bridge; and Z isa bond or —C(R^(4e))(R^(4e′))—, where R^(4e) and R^(4e′) are eachindependently hydrogen or an optionally substituted (C₁-C₆)alkyl, oreither R^(4e) or R^(4e′) taken together with R^(4c) or R^(4c′) forms abond, a methylene bridge or an ethylene bridge; a pharmaceuticallyacceptable salt thereof, or a solvate or hydrate of said compound orsaid salt.
 71. The compound of claim 70 wherein R^(4c) and R^(4c′) areeach hydrogen or either R^(4c) or R^(4c′) taken together with R^(4e) orR^(4e′) forms a bond; R^(4d) is hydrogen, hydroxy, amino, or a chemicalmoiety selected from the group consisting of (C₁-C₆)alkoxy, acyl,(C₁-C₆)alkylamino-, and di(C₁-C₄)alkylamino-; R^(4d′) is hydrogen, or achemical moiety selected from the group consisting of (C₁-C₆)alkyl andaryl, where said moiety is optionally substituted with one or moresubstituents; and R^(4e) and R^(4e′) are hydrogen or either R^(4e) orR^(4e′) taken together with R^(4c) or R^(4c′) forms a bond; apharmaceutically acceptable salt thereof, or a solvate or hydrate ofsaid compound or said salt.
 72. The compound of claim 69, 70, or 71wherein R^(0a), R^(0b), R^(1a), and R^(1b) are each independentlyselected from the group consisting of halo, (C₁-C₄)alkoxy, (C₁-C₄)alkyl,halo-substituted (C₁-C₄)alkyl, and cyano; a pharmaceutically acceptablesalt thereof, or a solvate or hydrate of said compound or said salt. 73.The compound of claim 72 wherein R^(0a), R^(0b), R^(1a), and R^(1b) areeach independently selected from the group consisting of chloro, fluoro,(C₁-C₄)alkoxy, (C₁-C₄)alkyl, fluoro-substituted (C₁-C₄)alkyl), andcyano; and n and m are each independently 0 or 1; a pharmaceuticallyacceptable salt thereof, or a solvate or hydrate of said compound orsaid salt.
 74. The compound of claim 63 wherein R^(4b), R^(4b′), R^(4f),and R^(4f′) are all hydrogen; and R^(4d) and R^(4d′) taken together forma 3-6 membered partially or fully saturated carbocyclic ring, a 3-6membered partially or fully saturated heterocyclic ring, a 5-6 memberedlactone ring, or a 4-6 membered lactam ring, where said carbocyclicring, said heterocyclic ring, said lactone ring and said lactam ring areoptionally substituted with one or more substituents and said lactonering or said lactam ring optionally contains an additional heteroatomselected from oxygen, nitrogen or sulfur; a pharmaceutically acceptablesalt thereof, or a solvate or hydrate of said compound or said salt. 75.The compound of claim 74 wherein X is a bond, —CH₂CH₂— or—C(R^(4c))(R^(4c′))—, where R^(4c) and R^(4c′) are each independentlyhydrogen or an optionally substituted (C₁-C₆)alkyl, or either R^(4c) orR^(4c′) taken together with R^(4e) or R^(4e′) forms a bond, a methylenebridge or an ethylene bridge; and Z is a bond, —CH₂CH₂— or—C(R^(4e))(R^(4e′))—, where R^(4e) and R^(4e′) are each independentlyhydrogen or an optionally substituted (C₁-C₆)alkyl, or either R^(4e) orR^(4e′) taken together with R^(4c) or R^(4c′) forms a bond, a methylenebridge or an ethylene bridge; a pharmaceutically acceptable saltthereof, or a solvate or hydrate of said compound or said salt.
 76. Thecompound of claim 75 wherein R^(4d) and R^(4d′) taken together form a5-6 membered lactam ring, where said lactam ring is optionallysubstituted with one or more substituents and optionally contains anadditional heteroatom selected from nitrogen or oxygen; apharmaceutically acceptable salt thereof, or a solvate or hydrate ofsaid compound or said salt.
 77. The compound of claim 76 wherein X is abond or C(R^(4c))(R^(4c′))—, where R^(4c) and R^(4c′) are each hydrogen;and Z is a bond or —C(R^(4e))(R^(4e′))—, where R^(4e) and R^(4e′) areeach hydrogen; a pharmaceutically acceptable salt thereof, or a solvateor hydrate of said compound or said salt.
 78. The compound of claim 74,75, 76 or 77 wherein R^(0a), R^(0b), R^(1a), and R^(1b) are eachindependently selected from the group consisting of halo, (C₁-C₄)alkoxy,(C₁-C₄)alkyl, halo-substituted (C₁-C₄)alkyl, and cyano; apharmaceutically acceptable salt thereof, or a solvate or hydrate ofsaid compound or said salt.
 79. The compound of claim 78 wherein R^(0a),R^(0b), R^(1a), and R^(1b) are each independently selected from thegroup consisting of chloro, fluoro, (C₁-C₄)alkoxy, (C₁-C₄)alkyl,fluoro-substituted (C₁-C₄)alkyl), and cyano; n and m are eachindependently 0 or 1; a pharmaceutically acceptable salt thereof, or asolvate or hydrate of said compound or said salt.
 80. The compound ofclaim 55 wherein R⁴ is a group of Formula (IB);

where R^(4a) is as defined in claim 43; R^(4b) is hydrogen, cyano,hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a 3-6 membered partially or fully saturated heterocycle, anda partially or fully saturated carbocyclic ring, where said moiety isoptionally substituted with one or more substituents, R^(4b′) ishydrogen, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6membered partially or fully saturated heterocycle, and a partially orfully saturated carbocyclic ring, where said moiety is optionallysubstituted with one or more substituents, or R^(4b) or R^(4b′) takentogether with R^(4e), R^(4e′), R^(4f), or R^(4′) forms a bond, amethylene bridge, or an ethylene bridge; X is a bond, —CH₂CH₂— or—C(R^(4c))(R^(4c′))—, where R^(4c) is hydrogen, cyano, hydroxy, amino,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a partiallyor fully saturated carbocyclic ring, where said moiety is optionallysubstituted with one or more substituents, or R^(4c) taken together withR^(4e), R^(4e′), R^(4f), or R^(4f′) forms a bond, a methylene bridge, oran ethylene bridge, and R^(4c′) is hydrogen, H₂NC(O)—, or a chemicalmoiety selected from the group consisting of (C₁-C₆)alkyl, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,aryl, heteroaryl, a 3-6 membered partially or fully saturatedheterocycle, and a partially or fully saturated carbocyclic ring, wheresaid moiety is optionally substituted with one or more substituents, orR^(4c′) taken together with R^(4e), R^(4e′), R^(4f), or R^(4f′) forms abond, a methylene bridge, or an ethylene bridge; Y is oxygen, sulfur,—C(O)—, or —C(R^(4d))(R^(4d′))—, where R^(4d) is hydrogen, cyano,hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a 3-6 membered partially or fully saturated heterocycle, anda partially or fully saturated carbocyclic ring, where said moiety isoptionally substituted with one or more substituents, and R^(4d′) ishydrogen, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C, —C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6membered partially or fully saturated heterocycle, and a partially orfully saturated carbocyclic ring, where said moiety is optionallysubstituted with one or more substituents, or R^(4d) and R^(4d′) takentogether form a 3-6 membered partially or fully saturated carbocyclicring, a 3-6 membered partially or fully saturated heterocyclic ring, a5-6 membered lactone ring, or a 4-6 membered lactam ring, where saidcarbocyclic ring, said heterocyclic ring, said lactone ring and saidlactam ring are optionally substituted with one or more substituents andsaid lactone ring and said lactam ring optionally contain an additionalheteroatom selected from oxygen, nitrogen or sulfur; Y is —NR^(4d″)—,where R^(4d″) is a hydrogen or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₃)alkylsulfonyl-,(C₁-C₃)alkylaminosulfonyl-, di(C₁-C₃)alkylaminosulfonyl-, acyl,(C₁-C₆)alkyl-O—C(O)—, aryl, and heteroaryl, where said moiety isoptionally substituted with one or more substituents; Z is a bond,—CH₂CH₂—, or C(R^(4e))(R^(4e′))—, where R^(4e) is hydrogen, cyano,hydroxy, amino, H₂NC(O)—, or a chemical moiety selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxy, acyloxy, acyl,(C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—,(C₁-C₆)alkylamino-, ((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-,acylamino-, aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl,heteroaryl, a 3-6 membered partially or fully saturated heterocycle, anda partially or fully saturated carbocyclic ring, where said moiety isoptionally substituted with one or more substituents, or R^(4e) takentogether with R^(4b), R^(4b′), R^(4c), or R^(4c′) forms a bond, amethylene bridge, or an ethylene bridge, and R^(4e′) is hydrogen,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6 membered partially orfully saturated heterocycle, and a partially or fully saturatedcarbocyclic ring, where said moiety is optionally substituted with oneor more substituents, or R^(4e′) taken together with R^(4b), R^(4b′),R^(4c), or R^(4c′) forms a bond, a methylene bridge, or an ethylenebridge; R^(4f) is hydrogen, cyano, hydroxy, amino, H₂NC(O)—, or achemical moiety selected from the group consisting of (C₁-C₆)alkyl,(C₁-C₆)alkoxy, acyloxy, acyl, (C₁-C₃)alkyl-O—C(O)—,(C₁-C₄)alkyl-NH—C(O)—, (C₁-C₄)alkyl)₂N—C(O)—, (C₁-C₆)alkylamino-,((C₁-C₄)alkyl)₂amino-, (C₃-C₆)cycloalkylamino-, acylamino-,aryl(C₁-C₄)alkylamino-, heteroaryl(C₁-C₄)alkylamino-, aryl, heteroaryl,a 3-6 membered partially or fully saturated heterocycle, and a partiallyor fully saturated carbocyclic ring, where said moiety is optionallysubstituted with one or more substituents; and R^(4f′) is hydrogen,H₂NC(O)—, or a chemical moiety selected from the group consisting of(C₁-C₆)alkyl, acyl, (C₁-C₃)alkyl-O—C(O)—, (C₁-C₄)alkyl-NH—C(O)—,(C₁-C₄)alkyl)₂N—C(O)—, aryl, heteroaryl, a 3-6 membered partially orfully saturated heterocycle, and a partially or fully saturatedcarbocyclic ring, where said moiety is optionally substituted with oneor more substituents, or R^(4f) or R^(4f′) taken together with R^(4b),R^(4b′), R^(4c), or R^(4c′) forms a bond, a methylene bridge, or anethylene bridge; a pharmaceutically acceptable salt thereof, or asolvate or hydrate of said compound or said salt.
 81. The compound ofclaim 80 wherein R^(4a), R^(4b), R^(4b′), R^(4f) and R^(4f′) are eachhydrogen; a pharmaceutically acceptable salt thereof, or a solvate orhydrate of said compound or said salt.
 82. The compound of claim 81wherein X is a bond, —CH₂CH₂— or —C(R^(4c))(R^(4c′))—, where R^(4c) andR^(4c′) are each independently hydrogen or (C₁-C₆)alkyl; Y is—NR^(4d″)—, where R^(4d″) is hydrogen or a chemical moiety selected fromthe group consisting of (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₁-C₃)alkylsulfonyl-, (C₁-C₃)alkylaminosulfonyl-,di(C₁-C₃)alkylaminosulfonyl-, acyl, (C₁-C₆)alkyl-O—C(O)—, aryl, andheteroaryl, where said moiety is optionally substituted with one or moresubstituents; Z is a bond, —CH₂CH₂— or —C(R^(4c))(R^(4c′))—, whereR^(4c) and R^(4c′) are each independently hydrogen or (C₁-C₆)alkyl; apharmaceutically acceptable salt thereof, or a solvate or hydrate ofsaid compound or said salt.
 83. The compound of claim 81 or 82 whereinR^(0a), R^(0b), R^(1a) and R^(1b) are each independently selected fromthe group consisting of halo, (C₁-C₄)alkoxy, (C₁-C₄)alkyl,halo-substituted (C₁-C₄)alkyl, and cyano; a pharmaceutically acceptablesalt thereof, or a solvate or hydrate of said compound or said salt. 84.The compound of claim 83 wherein R^(0a), R^(0b), R^(1a) and R^(1b) areeach independently selected from the group consisting of chloro, fluoro,(C₁-C₄)alkoxy, (C₁-C₄)alkyl, fluoro-substituted (C₁-C₄)alkyl), andcyano; and n and m are each independently 0 or 1; a pharmaceuticallyacceptable salt thereof, or a solvate or hydrate of said compound orsaid salt.
 85. The compound of claim 55 wherein R⁴ is a group havingFormula (IC)

where R⁵ and R⁶ are each independently hydrogen, aryl or (C₁-C₄)alkyl,and R⁷ is (C₁-C₄)alkyl-, halo-substituted (C₁-C₄)alkyl-,(C₁-C₄)alkoxy(C₁-C₄)alkyl-, (C₁-C₄)alkylamino(C₁-C₄)alkyl-,di(C₁-C₄)alkylamino(C₁-C₄)alkyl-, or a 4-6 membered partially or fullysaturated heterocylic ring containing 1 to 2 heteroatoms independentlyselected from oxygen, sulfur or nitrogen, or R⁵ and R⁶, or R⁵ and R⁷taken together form a 5-6 membered lactone, 4-6 membered lactam, or a4-6 membered partially or fully saturated heterocycle containing 1 to 2heteroatoms independently selected from oxygen, sulfur or nitrogen,where said lactone, said lactam and said heterocycle are optionallysubstituted with one or more substituents; a pharmaceutically acceptablesalt thereof, or a solvate or hydrate of said compound or said salt. 86.The compound of claim 85 wherein n and m are each independently 1 or 0;a pharmaceutically acceptable salt thereof, or a solvate or hydrate ofsaid compound or said salt.
 87. The compound of claim 86 wherein R⁵ andR⁶ are each independently hydrogen or (C₁-C₄)alkyl, and R⁷ is(C₁-C₄)alkyl; a pharmaceutically acceptable salt thereof, or a solvateor hydrate of said compound or said salt.
 88. The compound of claim 86or 87 wherein R^(0a), R^(0b), R^(1a), and R^(1b) are each independentlychloro, fluoro or trifluoromethyl; a pharmaceutically acceptable saltthereof, or a solvate or hydrate of said compound or said salt.
 89. Thecompound of claim 55 wherein R⁴ is an amino group having attachedthereto at least one chemical moiety selected from the group consistingof (C₁-C₈)alkyl, aryl, aryl(C₁-C₄)alkyl, a 3-8 membered partially orfully saturated carbocyclic ring, hydroxy(C₁-C₆)alkyl,(C₁-C₃)alkoxy(C₁-C₆)alkyl, heteroaryl(C₁-C₃)alkyl, and a partially orfully saturated heterocycle, where said chemical moiety is optionallysubstituted with one or more substituents; a pharmaceutically acceptablesalt thereof, or a solvate or hydrate of said compound or said salt. 90.The compound of claim 89 wherein n and m are each independently 1 or 0;a pharmaceutically acceptable salt thereof, or a solvate or hydrate ofsaid compound or said salt.
 91. The compound of claim 89 or 90 whereinR^(0a), R^(0b), R^(1a), and R^(1b) are each independently chloro, fluoroor trifluoromethyl; a pharmaceutically acceptable salt thereof, or asolvate or hydrate of said compound or said salt.
 92. The compound ofclaim 55 wherein R⁴ is an (C₁-C₆)alkyl group having attached thereto atleast one chemical moiety selected from the group consisting of hydroxy,(C₁-C₆)alkoxy, amino, (C₁-C₆)alkylamino,di((C₁-C₆)alkyl)amino(C₁-C₃)alkylsulfonyl, (C₁-C₃)alkylsulfamyl,di((C₁-C₃)alkyl)sulfamyl, acyloxy, a partially or fully saturatedheterocycle, and a partially or fully saturated carbocyclic ring, wheresaid chemical moiety is optionally substituted with one or moresubstituents; a pharmaceutically acceptable salt thereof, or a solvateor hydrate of said compound or said salt.
 93. The compound of claim 92wherein n and m are each independently 1 or 0; a pharmaceuticallyacceptable salt thereof, or a solvate or hydrate of said compound orsaid salt.
 94. The compound of claim 92 or 93 wherein R^(0a), R^(0b),R^(1a), and R^(1b) are each independently chloro, fluoro ortrifluoromethyl; a pharmaceutically acceptable salt thereof, or asolvate or hydrate of said compound or said salt.
 95. A pharmaceuticalcomposition comprising (1) a compound of claim 1, or a solvate orhydrate of said compound or said salt; and (2) a pharmaceuticallyacceptable excipient, diluent, or carrier.
 96. The composition of claim95 further comprising at least one additional pharmaceutical agent. 97.The composition of claim 96 wherein said additional pharmaceutical agentis a nicotine receptor partial agonist, an opioid antagonist, adopaminergic agent, an attention deficit disorder agent, or ananti-obesity agent.
 98. The composition of claim 97 wherein saidanti-obesity agent is selected from the group consisting of an apo-B/MTPinhibitor, a 11β-hydroxy steroid dehydrogenase-1 inhibitor, peptideYY₃₋₃₆ or an analog thereof, a MCR-4 agonist, a CCK-A agonist, amonoamine reuptake inhibitor, a sympathomimetic agent, a β₃ adrenergicreceptor agonist, a dopamine agonist, a melanocyte-stimulating hormonereceptor analog, a 5-HT2c receptor agonist, a melanin concentratinghormone antagonist, leptin, a leptin analog, a leptin receptor agonist,a galanin antagonist, a lipase inhibitor, a bombesin agonist, aneuropeptide-Y receptor antagonist, a thyromimetic agent,dehydroepiandrosterone or analog thereof, a glucocorticoid receptorantagonist, an orexin receptor antagonist, a glucagon-like peptide-1receptor agonist, a ciliary neurotrophic factor, a human agouti-relatedprotein antagonist, a ghrelin receptor antagonist, a histamine 3receptor antagonist or inverse agonist, and a neuromedin U receptoragonist.
 99. A method for treating a disease, condition or disorderwhich is modulated by a cannabinoid receptor antagonist in animalscomprising the step of administering to an animal in need of suchtreatment a therapeutically effective amount of a compound of claim 1; apharmaceutically acceptable salt thereof, or a solvate or hydrate ofsaid compound or said salt.
 100. The method of claim 99 wherein saidcompound is a compound of claim 2, a pharmaceutically acceptable saltthereof, or a solvate or hydrate of said compound or said salt.
 101. Themethod of claim 99 wherein said compound is administered in combinationwith a nicotine receptor partial agonist, an opioid antagonist, adopaminergic agent, an attention deficit disorder agent, or ananti-obesity agent.
 102. The method of claim 100 wherein said compoundis administered in combination with a nicotine receptor partial agonist,an opioid antagonist, a dopaminergic agent, an attention deficitdisorder agent, or an anti-obesity agent.
 103. The method of claim 101or 102 wherein said anti-obesity agent is selected from the groupconsisting of an apo-B/MTP inhibitor, a 11β-hydroxy steroiddehydrogenase-1 inhibitor, peptide YY₃₋₃₆ or an analog thereof, a MCR-4agonist, a CCK-A agonist, a monoamine reuptake inhibitor, asympathomimetic agent, a β₃ adrenergic receptor agonist, a dopamineagonist, a melanocyte-stimulating hormone receptor analog, a 5-HT2creceptor agonist, a melanin concentrating hormone antagonist, leptin, aleptin analog, a leptin receptor agonist, a galanin antagonist, a lipaseinhibitor, a bombesin agonist, a neuropeptide-Y receptor antagonist, athyromimetic agent, dehydroepiandrosterone or analog thereof, aglucocorticoid receptor antagonist, an orexin receptor antagonist, aglucagon-like peptide-1 receptor agonist, a ciliary neurotrophic factor,a human agouti-related protein antagonist, a ghrelin receptorantagonist, a histamine 3 receptor antagonist or inverse agonist, and aneuromedin U receptor agonist.
 104. The method of claim 99 or 100wherein said disease, condition or disorder modulated by a cannabinoidreceptor antagonist is selected from the group consisting of weightloss, obesity, bulimia, depression, atypical depression, bipolardisorders, psychoses, schizophrenia, behavioral addictions, suppressionof reward-related behaviors, alcoholism, tobacco abuse, dementia,seizure disorders, epilepsy, attention deficit disorder, Parkinson'sdisease, inflammation, gastrointestinal disorders, and type II diabetes.105. The method of claim 104 wherein said disease, condition or disordermodulated by a cannabinoid receptor antagonist is obesity, bulimia,attention deficit disorder, Parkinson's disease, dementia, alcoholism,or tobacco abuse.
 106. A method for treating a disease, condition ordisorder modulated by a cannabinoid receptor antagonist comprising thestep of administering a pharmaceutical composition of claim
 95. 107. Themethod of claim 106 wherein said pharmaceutical composition furthercomprises an additional pharmaceutical agent.
 108. The method of claim107 wherein said additional pharmaceutical agent is a nicotine partialagonist, an opioid antagonist, a dopaminergic agent, an attentiondeficit disorder agent, or an anti-obesity agent.
 109. The method ofclaim 108 wherein said anti-obesity agent is selected from the groupconsisting of an apo-B/MTP inhibitor, a 11β-hydroxy steroiddehydrogenase-1 inhibitor, peptide YY336 or an analog thereof, a MCR-4agonist, a CCK-A agonist, a monoamine reuptake inhibitor, asympathomimetic agent, a β₃ adrenergic receptor agonist, a dopamineagonist, a melanocyte-stimulating hormone receptor analog, a 5-HT2creceptor agonist, a melanin concentrating hormone antagonist, leptin, aleptin analog, a leptin receptor agonist, a galanin antagonist, a lipaseinhibitor, a bombesin agonist, a neuropeptide-Y receptor antagonist, athyromimetic agent, dehydroepiandrosterone or analog thereof, aglucocorticoid receptor antagonist, an orexin receptor antagonist, aglucagon-like peptide-1 receptor agonist, a ciliary neurotrophic factor,a human agouti-related protein antagonist, a ghrelin receptorantagonist, a histamine 3 receptor antagonist or inverse agonist, and aneuromedin U receptor agonist.
 110. The method of claim 106, 107, 108 or109 wherein said disease, condition or disorder modulated by acannabinoid receptor antagonist is obesity, bulimia, attention deficitdisorder, Parkinson's disease, dementia, alcoholism, or tobacco abuse.111. A method for treating a disease, condition or disorder which ismodulated by a cannabinoid receptor antagonist in animals comprising thestep of administering to an animal in need of such treatment atherapeutically effective amount of a compound of claim 55; apharmaceutically acceptable salt thereof, or a solvate or hydrate ofsaid compound or said salt.
 112. The method of claim 111 wherein saidcompound is a compound of claim 56, a pharmaceutically acceptable saltthereof, or a solvate or hydrate of said compound or said salt.
 113. Themethod of claim 111 wherein said compound is administered in combinationwith a nicotine partial agonist, an opioid antagonist, a dopaminergicagent, an attention deficit disorder agent, or an anti-obesity agent.114. The method of claim 112 wherein said compound is administered incombination with a nicotine partial agonist, an opioid antagonist, adopaminergic agent, an attention deficit disorder agent, or ananti-obesity agent.
 115. The method of claim 113 or 114 wherein saidanti-obesity agent is selected from the group consisting of an apo-B/MTPinhibitor, a 11β-hydroxy steroid dehydrogenase-1 inhibitor, peptideYY₃₋₃₆ or an analog thereof, a MCR-4 agonist, a CCK-A agonist, amonoamine reuptake inhibitor, a sympathomimetic agent, a β₃ adrenergicreceptor agonist, a dopamine agonist, a melanocyte-stimulating hormonereceptor analog, a 5-HT2c receptor agonist, a melanin concentratinghormone antagonist, leptin, a leptin analog, a leptin receptor agonist,a galanin antagonist, a lipase inhibitor, a bombesin agonist, aneuropeptide-Y receptor antagonist, a thyromimetic agent,dehydroepiandrosterone or analog thereof, a glucocorticoid receptorantagonist, an orexin receptor antagonist, a glucagon-like peptide-1receptor agonist, a ciliary neurotrophic factor, a human agouti-relatedprotein antagonist, a ghrelin receptor antagonist, a histamine 3receptor antagonist or inverse agonist, and a neuromedin U receptoragonist.
 116. The method of claim 111 or 112 wherein said disease,condition or disorder modulated by a cannabinoid receptor antagonist isselected from the group consisting of weight loss, obesity, bulimia,depression, atypical depression, bipolar disorders, psychoses,schizophrenia, behavioral addictions, suppression of reward-relatedbehaviors, alcoholism, tobacco abuse, dementia, seizure disorders,epilepsy, attention deficit disorder, Parkinson's disease, inflammation,gastrointestinal disorders, and type II diabetes.
 117. The method ofclaim 116 wherein said disease, condition or disorder modulated by acannabinoid receptor antagonist is obesity, bulimia, attention deficitdisorder, Parkinson's disease, dementia, alcoholism, or tobacco abuse.118. A method for treating a disease, condition or disorder modulated bya cannabinoid receptor antagonist in animals comprising the step ofadministering to an animal in need of such treatment two separatepharmaceutical compositions comprising (i) a first compositioncomprising a compound of claim 1 or claim 55, or a pharmaceuticallyacceptable salt thereof or a solvate or hydrate of said salt, and apharmaceutically acceptable excipient, diluent, or carrier, and (ii) asecond composition comprising at least one additional pharmaceuticalagent and a pharmaceutically acceptable excipient, diluent, or carrier.119. The method of claim 118 wherein said at least one additionalpharmaceutical agent is a nicotine partial agonist, an opioidantagonist, a dopaminergic agent, an attention deficit disorder agent,or an anti-obesity agent.
 120. The method of claim 119 wherein saidanti-obesity agent is selected from the group consisting of an apo-B/MTPinhibitor, a 11β-hydroxy steroid dehydrogenase-1 inhibitor, peptideYY₃₋₃₆ or an analog thereof, a MCR-4 agonist, a CCK-A agonist, amonoamine reuptake inhibitor, a sympathomimetic agent, a β₃ adrenergicreceptor agonist, a dopamine agonist, a melanocyte-stimulating hormonereceptor analog, a 5-HT2c receptor agonist, a melanin concentratinghormone antagonist, leptin, a leptin analog, a leptin receptor agonist,a galanin antagonist, a lipase inhibitor, a bombesin agonist, aneuropeptide-Y receptor antagonist, a thyromimetic agent,dehydroepiandrosterone or analog thereof, a glucocorticoid receptorantagonist, an orexin receptor antagonist, a glucagon-like peptide-1receptor agonist, a ciliary neurotrophic factor, a human agouti-relatedprotein antagonist, a ghrelin receptor antagonist, a histamine 3receptor antagonist or inverse agonist, and a neuromedin U receptoragonist.
 121. The method of claim 118 wherein said first composition andsaid second composition are administered simultaneously.
 122. The methodof claim 118 wherein said first composition and said second compositionare administered sequentially and in any order.
 123. A compound ofFormula (1c), (1d), (2e), (2f or (2g)

wherein R⁰, R¹, R², R³ are as defined in claim 1; R is an alkyl group;Pg is an amino-protecting group; and L is a leaving group.